MICALs (for Molecule Interacting with CasL) form a recently discovered family of evolutionary conserved signal transduction proteins. They contain multiple well-conserved domains known for interactions with the cytoskeleton, cytoskeletal adaptor proteins, and other signaling proteins. In addition to their ability to bind other proteins, MICALs contain a large NADPH-dependent flavoprotein monooxygenase enzymatic domain. Although MICALs have already been implicated in a variety of cellular processes, their function during axonal pathfinding in the Drosophila neuromuscular system has been best characterized. During the establishment of neuromuscular connectivity in the fruit fly, MICAL binds the axon guidance receptor Plexin A and transduces semaphorin-1a-mediated repulsive axon guidance. Intriguingly, mutagenesis and pharmacological inhibitor studies suggest a role for MICAL flavoenzyme redox functions in semaphorin/plexin-mediated axonal pathfinding events. This review summarizes our current understanding of MICALs, with an emphasis on their role in semaphorin signaling.