Regulation of skeletal muscle determination and differentiation in vertebrates centers on a core regulatory network which is composed of two families of transcription factors, the MyoD group basic helix-loop-helix (bHLH) muscle regulatory factors (MRFs) and the myocyte enhancer factor 2 (MEF2) group of MADS-box regulators. Members of this network interact with each other genetically and physically, and together they cooperate to positively regulate transcription of downstream muscle-specific differentiation genes. During development, the myogenic network can be activated or repressed in response to patterning signals, some of which have recently been identified. Once activated, the powerful myogenic activity of the core network can be modulated and held in check by a remarkably large group of negative regulators that operate on network components by diverse mechanisms. Recent discoveries highlight extensive parallels between myogenesis and peripheral neurogenesis in the structures of their respective regulatory networks and in the interaction of their bHLH networks with other regulatory circuits. Comparisons with Drosophila indicate that these ensembles of interacting molecular circuits have been highly conserved during evolution.