The article discusses how mechanical forces play a crucial role in directing stem cell behavior during development and regeneration. Stem cells interact with their microenvironment, or niche, through mechanical cues that regulate cell fate and behavior. These forces are essential during embryonic development, where they contribute to patterning and organogenesis. The physical environment of pluripotent stem cells influences their differentiation and self-renewal, while adult stem cells require physical interactions with the extracellular matrix (ECM) to maintain their potency. In vitro, synthetic models of the stem cell niche allow for precise control of biophysical and biochemical properties, enabling the study of how mechanical cues like matrix stiffness or applied forces direct stem cell differentiation and function. Understanding the mechanobiology of stem cells informs the design of artificial niches for regenerative therapies. Mechanical cues are generated and resisted across various scales, from sub-cellular to organismal levels. These cues, whether intracellularly generated or externally applied, significantly impact stem cell function. Mechanical interactions mediated by adhesion to the ECM and cell-cell junctions transmit forces that regulate intracellular signaling pathways. The microenvironment, composed of fluids, solids, gases, or other cells, provides resistance or compliance that may store or dissipate forces. Developing systems to control and decouple these mechanical cues is essential for understanding their effects on stem cells. The article also highlights the importance of mechanical properties such as stress, strain, elasticity, and viscoelasticity in understanding how cells respond to their environment. It discusses how mechanical forces regulate stem cell behavior, including differentiation, self-renewal, and function. The study of mechanobiology is complex, as mechanical stimuli affect multiple aspects of cell behavior, including matrix traction forces, membrane curvature, growth factor signaling, and cell fate. The physical properties of the ECM regulate mammary gland morphogenesis in vitro, and matrix stiffness affects biochemical signals during angiogenesis. The article explores the manipulation of mechanobiology through engineered systems that interface with stem cells in vitro. These systems allow for the study of how mechanical cues regulate stem cell behavior. Challenges include achieving independent control of various physical and chemical properties of the synthetic niche. Synthetic niches, such as hydrogels and decellularized tissues, provide defined microenvironments for in vitro studies. The article emphasizes the importance of considering both elastic and viscoelastic properties of synthetic niches, as natural matrices exhibit viscoelastic behavior. The application of extrinsic forces to directly probe mechanoresponses is discussed, including the use of micro-scale probes and microfluidics to apply and measure mechanical forces on cells. The article also addresses how stem cells respond to mechanical cues through mechanosensing and mechanotransduction, affecting proliferation, self-renewal, and differentiation. It highlights the role of integrin receptors, mechanosensitive ion channels, and the primary cilium in these processes. The article concludes with the application of mechanical cues in regenerative medicine, emphasizing the importance of controlling stem cellThe article discusses how mechanical forces play a crucial role in directing stem cell behavior during development and regeneration. Stem cells interact with their microenvironment, or niche, through mechanical cues that regulate cell fate and behavior. These forces are essential during embryonic development, where they contribute to patterning and organogenesis. The physical environment of pluripotent stem cells influences their differentiation and self-renewal, while adult stem cells require physical interactions with the extracellular matrix (ECM) to maintain their potency. In vitro, synthetic models of the stem cell niche allow for precise control of biophysical and biochemical properties, enabling the study of how mechanical cues like matrix stiffness or applied forces direct stem cell differentiation and function. Understanding the mechanobiology of stem cells informs the design of artificial niches for regenerative therapies. Mechanical cues are generated and resisted across various scales, from sub-cellular to organismal levels. These cues, whether intracellularly generated or externally applied, significantly impact stem cell function. Mechanical interactions mediated by adhesion to the ECM and cell-cell junctions transmit forces that regulate intracellular signaling pathways. The microenvironment, composed of fluids, solids, gases, or other cells, provides resistance or compliance that may store or dissipate forces. Developing systems to control and decouple these mechanical cues is essential for understanding their effects on stem cells. The article also highlights the importance of mechanical properties such as stress, strain, elasticity, and viscoelasticity in understanding how cells respond to their environment. It discusses how mechanical forces regulate stem cell behavior, including differentiation, self-renewal, and function. The study of mechanobiology is complex, as mechanical stimuli affect multiple aspects of cell behavior, including matrix traction forces, membrane curvature, growth factor signaling, and cell fate. The physical properties of the ECM regulate mammary gland morphogenesis in vitro, and matrix stiffness affects biochemical signals during angiogenesis. The article explores the manipulation of mechanobiology through engineered systems that interface with stem cells in vitro. These systems allow for the study of how mechanical cues regulate stem cell behavior. Challenges include achieving independent control of various physical and chemical properties of the synthetic niche. Synthetic niches, such as hydrogels and decellularized tissues, provide defined microenvironments for in vitro studies. The article emphasizes the importance of considering both elastic and viscoelastic properties of synthetic niches, as natural matrices exhibit viscoelastic behavior. The application of extrinsic forces to directly probe mechanoresponses is discussed, including the use of micro-scale probes and microfluidics to apply and measure mechanical forces on cells. The article also addresses how stem cells respond to mechanical cues through mechanosensing and mechanotransduction, affecting proliferation, self-renewal, and differentiation. It highlights the role of integrin receptors, mechanosensitive ion channels, and the primary cilium in these processes. The article concludes with the application of mechanical cues in regenerative medicine, emphasizing the importance of controlling stem cell