We examined acute molecular responses in skeletal muscle to divergent exercise stimuli by combining consecutive bouts of resistance and endurance exercise. Eight men (22.9 ± 6.3 yr, body mass 73.2 ± 4.5 kg, VO_2peak 54.0 ± 5.7 mL^.kg^-1.min^-1) were randomly assigned to complete trials consisting of either resistance exercise (8 x 5 leg extension, 80% 1RM) followed by a bout of endurance exercise (30 min cycling, 70% VO_2peak), or vice-versa. Muscle biopsies were obtained from the vastus lateralis at rest, 15 min after each exercise bout and following 3 h of passive recovery to determine early signaling and mRNA responses. Phosphorylation of Akt and Akt1 ^ser473 were elevated 15 min after resistance exercise but not cycling, with the greatest increase observed when resistance exercise followed cycling (~55%, P<0.01). TSC2-mTOR-S6K phosphorylation 15 min following each bout of exercise was similar regardless of exercise mode. The cumulative effect of combined exercise resulted in disparate mRNA responses. IGF-I mRNA content was reduced when cycling preceded resistance exercise (-42%) while MuRF mRNA was elevated when cycling was undertaken after resistance exercise (~52%, P<0.05). The HKII mRNA level was higher following resistance-cycling (~45%, P<0.05) than cycling-resistance exercise, while modest increases in PGC-1 mRNA did not reveal an order effect. We conclude that acute responses to diverse bouts of contractile activity are modified by the exercise order. Moreover, undertaking divergent exercise in close proximity influences the acute molecular profile and likely exacerbates "adaptation interference".