Skeletal muscle from strength‐ and endurance‐trained individuals represents diverse adaptive states. In this regard, AMPK‐PGC‐1α signaling mediates several adaptations to endurance training, while up‐regulation of the Akt‐TSC2‐mTOR pathway may underlie increased protein synthesis after resistance exercise. We determined the effect of prior training history on signaling responses in seven strength‐trained and six endurance‐trained males who undertook 1 h cycling at 70% VO2peak or eight sets of five maximal repetitions of isokinetic leg extensions. Muscle biopsies were taken at rest, immediately and 3 h postexercise. AMPK phosphorylation increased after cycling in strength‐trained (54%; P<0.05) but not endurance‐trained subjects. Conversely, AMPK was elevated after resistance exercise in endurance‐ (114%; P<0.05), but not strength‐trained subjects. Akt phosphorylation increased in endurance‐ (50%; P<0.05), but not strength‐trained subjects after cycling but was unchanged in either group after resistance exercise. TSC2 phosphorylation was decreased (47%; P<0.05) in endurance‐trained subjects following resistance exercise, but cycling had little effect on the phosphorylation state of this protein in either group. p70S6K phosphorylation increased in endurance‐ (118%; P<0.05), but not strength‐trained subjects after resistance exercise, but was similar to rest in both groups after cycling. Similarly, phosphorylation of S6 protein, a substrate for p70 S6K, was increased immediately following resistance exercise in endurance‐ (129%; P<0.05), but not strength‐trained subjects. In conclusion, a degree of “response plasticity” is conserved at opposite ends of the endurance‐hypertrophic adaptation continuum. Moreover, prior training attenuates the exercise specific signaling responses involved in single mode adaptations to training.