The molecular mechanisms controlling -adrenergic receptor agonists (BA) - induced skeletal muscle hypertrophy are not well known. Here, we report that BA exerts a distinct muscle- and muscle fiber type-specific hypertrophy that is preferentially restricted to fast-twitch fibers. We show herein that pharmacologically or genetically attenuating extracellular signal-regulated kinase (ERK) signaling in muscle fibers resulted in decreases (P < 0.05) in fast but not slow fiber type-specific reporter gene expressions in response to BA exposure in vitro and in vivo. Consistent with these data, forced expression of MAPK phosphatase 1 (MKP-1), a nuclear protein that dephosphoryates ERK1/2, in fast-twitch skeletal muscle ablated (P < 0.05) hypertrophic effects of BA-feeding (clenbuterol, 20 ppm in water) in vivo. Further analysis showed that BA-induced phosphorylation and activation of ERK occurs to a greater (P < 0.05) extent in fast myofibers than in slow myofibers. Analysis of the basal level of ERK activity in slow and fast muscles revealed that ERK1/2 is activated to a greater extent in fast- than in slow-twitch muscles. These data indicate that ERK signaling is differentially involved in BA-induced hypertrophy in slow and fast skeletal muscles, suggesting that the increased abundance of phosphoERK1/2 and ERK activity found in fast-twitch myofibers, compared to their slow-twitch counterparts may account for, at least in part, the fiber-type-specific hypertrophy induced by BA stimulation. These data suggest fast myofibers are pivotal in the adaptation of muscle to environmental cues and that the mechanism underlying this change is partially mediated by the MAPK signaling cascade.