Throughout life, myoblast differentiation maintains and repairs muscle. The transcription factor MyoD, which is regulated by MyoD-interacting proteins, initiates myogenesis by controlling the temporal expression of myogenin and other muscle-specific regulatory genes. Now, Christina Mitchell and colleagues identify FHL3 as a MyoD-interacting protein that negatively regulates myogenesis (see p. 1423). FHL3, which is highly expressed in skeletal muscle, contains four and a half LIM domains, which mediate protein-protein interactions. The authors show that overexpression of FHL3 in the muscle cell line C2C12 retards myotube formation and decreases the expression of myogenin but not MyoD. By contrast, knocking down FHL3 by RNAi enhances myoblast differentiation and increases myogenin expression, again without altering MyoD expression. FHL3, the authors report, binds to MyoD and functions as its potent negative co-transcriptional regulator. They propose, therefore, that, when new muscle is needed, FHL3 is excluded from the nucleus, which relieves its negative regulation of MyoD and allows myogenesis to proceed.