Recent genetic and biochemical studies have demonstrated that skeletal muscle growth and differentiation in vertebrates are controlled by a core regulatory network which consists of two families of transcriptional 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. During development, MEF2 interacts genetically and physically with different members of this myogenic network and together they cooperate to positively or negatively regulate transcription of downstream muscle-specific differentiation genes. This paper reviews current understanding of molecular mechanism of these interactions and essential roles that MEF2 plays in skeletal muscle growth and differentiation during development.