The elucidation of the myogenic regulatory factors (MRFs) has resulted in a surge of research activity that promises to bridge molecular and embryological approaches to muscle research. In this review, we consider the arguments that would place MRFs in a key determination role for the skeletal muscle lineage in the vertebrate embryo. Amphibian, avian, and murine systems are compared and recent developments in the molecular embryology of myogenesis are reviewed. A model is proposed to account for the apparent discrepancies in conclusions drawn from studies using cultured cells that indicate a role for the MRFs in determination, and studies of MRF and muscle gene expression in vivo that indicate a role in differentiation but not in lineage determination.