Cadherins form a large family of membrane glycoproteins which mediate homophilic calcium-dependent cell adhesion. They are thought to mediate the initial calcium-dependent cell adhesion which precedes the plasma membrane fusion of skeletal myoblasts. Two cadherin subtypes are known to be expressed in mammalian skeletal myoblasts: muscle cadherin (M-cadherin) and neural cadherin (N-cadherin). In the present study we demonstrate that 1) the expression of Mand N-cadherin is differentially regulated during myoblast differentiation in vitro, 2) the expression of M-cadherin but not N-cadherin is inhibited by 5-bromo-2'-deoxyuridine (BUdR), an agent which selectively inhibits skeletal myoblast differentiation, and 3) fusion and differentiation-competent rat L, myoblasts do not express detectable levels of N-cadherin mRNA. In vivo, M-cadherin mRNA was detectable exclusively in skeletal muscle. M-cadherin mRNA levels peaked during the secondary myogenic wave in rat hindlimb muscle, becoming barely detectable in 1-week-old and adult rats. These observations indicate that M-cadherin is unique in two ways: It is the first cadherin to be included in the family of skeletal muscle-specific genes, and it shows peak levels of expression in developing skeletal muscle tissue. Taken together, these results suggest that M-cadherin plays an important role in skeletal myogenesis.