The article discusses the mechanisms underlying directional cell migration, which is a critical component of cell motility. While random cell movement is well understood, the complex regulation of directional migration remains less clear. The authors highlight that multiple factors, including extracellular matrix (ECM) topography, cellular polarity, receptor signaling, integrin trafficking, and actin-myosin contraction, converge to regulate Rho family GTPases and control lamellipodial protrusions, thereby promoting directional migration. They emphasize the importance of intracellular signaling, particularly at the leading edge, in regulating directional migration. The review also explores how the stability of protrusions at the leading edge, the topography of the ECM, and the molecular mechanisms driving each step of the cell motility cycle influence directional migration. Additionally, it discusses the role of polarity signaling machinery, such as the Par complex, in regulating directional migration, as well as the involvement of Wnt signaling and the cofilin pathway. The article concludes by highlighting the complexity of directional migration and the need for further research to understand the hierarchical or synergistic nature of the mechanisms involved.The article discusses the mechanisms underlying directional cell migration, which is a critical component of cell motility. While random cell movement is well understood, the complex regulation of directional migration remains less clear. The authors highlight that multiple factors, including extracellular matrix (ECM) topography, cellular polarity, receptor signaling, integrin trafficking, and actin-myosin contraction, converge to regulate Rho family GTPases and control lamellipodial protrusions, thereby promoting directional migration. They emphasize the importance of intracellular signaling, particularly at the leading edge, in regulating directional migration. The review also explores how the stability of protrusions at the leading edge, the topography of the ECM, and the molecular mechanisms driving each step of the cell motility cycle influence directional migration. Additionally, it discusses the role of polarity signaling machinery, such as the Par complex, in regulating directional migration, as well as the involvement of Wnt signaling and the cofilin pathway. The article concludes by highlighting the complexity of directional migration and the need for further research to understand the hierarchical or synergistic nature of the mechanisms involved.