Dystrophin is the approximately 400,000 Da. protein (p400K) product of the Duchenne muscular dystrophy gene locus. In the sarcolemma membrane, it is associated with several other proteins, many of which are glycoproteins (abbreviated gp) and include gp156K, p59K, gp50K, gp43K, gp35K, and p25K. Here, we show that dystrophin, gp156K, and p59K are calmodulin-binding proteins, the binding is Ca(2+)-dependent, and of high-affinity similar to that seen with calmodulin-activated enzymes. Two putative calmodulin-binding sequences were identified, one at either end of the dystrophin sequence.