This essay reviews the long tradition of experimental genetics of the Drosophila indirect flight muscles (IFM). It discusses how genetics can operate in tandem with multidisciplinary approaches to provide a description, in molecular terms, of the functional properties of the muscle myofibril. In particular, studies at the interface of genetics and proteomics address protein function at the cellular scale and offer an outstanding platform with which to elucidate how the myofibril works. Two generalizations can be enunciated from the studies reviewed. (...) First, the study of mutant IFM proteomes provides insight into how proteins are functionally organized in the myofibril. Second, IFM mutants can give rise to structural and contractile defects that are unrelated, a reflection of the dual function that myofibrillar proteins play as fundamental components of the sarcomeric framework and biochemical “parts” of the contractile “engine”. BioEssays 23:1047–1063, 2001. © 2001 John Wiley & Sons, Inc. (shrink)