In recent years, skeletal muscle has become an important model for understanding the mechanisms that regulate tissue-specific gene expression. The formation of skeletal muscle during embryogenesis involves commitment of mesodermal progenitors to the myogenic lineage and subsequent differentiation of skeletal myoblasts into terminally differentiated myotubes. Like many cell types, skeletal myoblasts do not express markers of terminal differentiation until they are forced to exit the cell cycle in response to environmental cues. Growth factor signals play a central role in regulating the program for muscle-specific transcription by maintaining myoblasts in a proliferative state that is nonpermissive for the expression of muscle-specific genes. Analysis of the mechanisms that regulate muscle differentiation in tissue culture led to the discovery of the four skeletal muscle-specific regulatory factors, MyoD (Davis et al. 1987), myogenin (Edmondson and Olson 1989; Wright et al. 1989), Myf5 (Braun et al. 1989a), and MRF4 (Rhodes and Konieczny 1989; Miner and Wold 1990; Braun et al. 1990), each of which can activate skeletal muscle gene transcription when expressed ectopically in a variety of nonmuscle cell types. Although many mammalian cell type-specific transcription factors have been identified, the myogenic factors are unique in their abilities to orchestrate an entire program of tissuespecific transcription when introduced into diverse cell types. This activity led to the notion that these factors function as master regulators of muscle cell fate during development. However, recent studies in which these genes have been inactivated through homologous recombination in transgenic mice have resulted in surprising phenotypes (or lack thereof) and have necessitated a reevaluation of the potential roles of these factors in the control of determination and differentiation in the myogenic lineage. Here, we review the models that emerged from studies of the myogenic factors in tissue culture and reconsider the potential functions of these factors in the embryo in light of recent gene-targeting experiments. For more comprehensive reviews on the control of muscle gene expression, the reader is referred to several recent reviews (Olson 1990, 1993; Weintraub et al. 1991;