For decades it has been debated how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha calcitonin gene-related peptide (aCGRP) known to be released from exercising skeletal muscles, is key at this remodeling. Indeed, aCGRP exposure yielded larger cardiac myocytes in culture whereas exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was improved in Mice overexpressing cardiac CGRP receptors (CLR-tg) while it was attenuated in aCGRP^-/- mice or CGRP(8-37) treated wt mice . Spontaneous activity, blood volume, total hemoglobin, muscle capillarization and fiber composition were all unaffected but heart index and ventricular myocyte volume were elevated in CLR-tg and reduced in aCGRP^-/- mice. Gene expression profiling of aCGRP^-/- (but not CLR-tg) hearts resembled the transcriptional changes seen in maladaptive cardiac hypertrophy. Thus, aCGRP released by skeletal muscles during exercise might be a hitherto unrecognized effector governing cardiac adaptations at the intersection of physiological and pathological stresses.