During the period 1960-1988, cell fate decisions were shown to be strongly influenced by spatial position within embryos and by biochemical cues, with embryo mixing, lineage tracing, and yolk sac colony assays linking position to differentiation outcomes. In vitro differentiation and embryoid-body-like organization demonstrated pluripotent, tissue-structured differentiation, while extracellular matrix components such as laminin and related cell-matrix interactions guided morphogenesis in aggregates and developing embryos. Growth factor signaling, including Transforming Growth Factor beta pathways, modulated myogenic and erythroid fates, illustrating pathway-specific control over lineage commitment and aligning gene-expression patterns with developmental programs. Historical Significance: This era reframed development as an environment- and signal-driven process, bridging in vivo spatial organization with in vitro systems to dissect lineage commitment, and establishing foundational concepts for stem cell biology and regenerative research. The unitarian theory of the origin of the four epithelial cell types in the mouse small intestine, the yolk sac origin of haemopoietic colonies, and the demonstration of germline transmission of cultured-cell traits underscored early mechanisms for lineage specification and genetic modification; the work on splicing of messenger RNA precursors highlighted molecular control of gene expression, while clonal differentiation studies in mast cells provided early proof of concept for lineage trajectories.