This review discusses the design of materials to direct stem-cell fate, focusing on both 2D and 3D biomaterials. Stem cells, defined by their ability to self-renew and differentiate, are crucial for tissue regeneration. However, their use is hindered by challenges that nature has evolved to overcome. Advanced biomaterials can mimic the body's natural microenvironments, promoting stem-cell differentiation or propagation without losing their stemness. The review highlights the importance of understanding both biochemical and biophysical cues in stem-cell niches, which are complex environments that regulate stem-cell behavior. 2D biomaterials allow the study of individual niche components, while 3D systems better replicate the complexity of natural tissues. The mechanical properties of the matrix, such as stiffness, significantly influence stem-cell fate, as demonstrated by studies showing that different stiffness levels affect cell differentiation and proliferation. Biomaterials can be used to create precise and controlled environments for stem-cell research, enabling the study of cell signaling, adhesion, and differentiation. Techniques such as microfluidics and microwell arrays allow for high-throughput analysis of stem-cell behavior. Additionally, biomaterials can be designed to deliver bioactive signals, enhancing stem-cell function and promoting tissue regeneration. The review also discusses the challenges in 3D culture, including the need for appropriate elasticity, nutrient diffusion, and the avoidance of physical barriers. Advances in bioprinting offer a promising approach to create complex 3D tissues, potentially revolutionizing tissue engineering. In vivo applications of biomaterials include delivering stem cells to damaged tissues and enhancing endogenous stem-cell function. These approaches hold significant promise for future clinical applications in regenerative medicine. Despite these advancements, challenges remain, including the identification of robust stem-cell markers and the analysis of large datasets generated by biomaterials platforms. Collaborative efforts between cell biologists and materials scientists are essential to address these challenges and advance stem-cell research towards clinical relevance.This review discusses the design of materials to direct stem-cell fate, focusing on both 2D and 3D biomaterials. Stem cells, defined by their ability to self-renew and differentiate, are crucial for tissue regeneration. However, their use is hindered by challenges that nature has evolved to overcome. Advanced biomaterials can mimic the body's natural microenvironments, promoting stem-cell differentiation or propagation without losing their stemness. The review highlights the importance of understanding both biochemical and biophysical cues in stem-cell niches, which are complex environments that regulate stem-cell behavior. 2D biomaterials allow the study of individual niche components, while 3D systems better replicate the complexity of natural tissues. The mechanical properties of the matrix, such as stiffness, significantly influence stem-cell fate, as demonstrated by studies showing that different stiffness levels affect cell differentiation and proliferation. Biomaterials can be used to create precise and controlled environments for stem-cell research, enabling the study of cell signaling, adhesion, and differentiation. Techniques such as microfluidics and microwell arrays allow for high-throughput analysis of stem-cell behavior. Additionally, biomaterials can be designed to deliver bioactive signals, enhancing stem-cell function and promoting tissue regeneration. The review also discusses the challenges in 3D culture, including the need for appropriate elasticity, nutrient diffusion, and the avoidance of physical barriers. Advances in bioprinting offer a promising approach to create complex 3D tissues, potentially revolutionizing tissue engineering. In vivo applications of biomaterials include delivering stem cells to damaged tissues and enhancing endogenous stem-cell function. These approaches hold significant promise for future clinical applications in regenerative medicine. Despite these advancements, challenges remain, including the identification of robust stem-cell markers and the analysis of large datasets generated by biomaterials platforms. Collaborative efforts between cell biologists and materials scientists are essential to address these challenges and advance stem-cell research towards clinical relevance.