Differentiation is the process by which a cell activates the expression of tissue-specific genes, downregulates the expression of potency markers, and acquires the phenotypic characteristics of its mature fate. The signals that regulate differentiation include biochemical and mechanical factors within the surrounding microenvironment. We describe recent breakthroughs in our understanding of the mechanical control mechanisms that regulate differentiation, with a specific emphasis on the differentiation events that build the early mouse embryo. Engineering approaches that reproducibly mimic the mechanical regulation of differentiation will permit new insights into early development and applications in regenerative medicine.