Recent reports suggest that aerobic exercise may boost the hypertrophic response to short-term resistance training. This study explored the effects of an acute aerobic exercise bout on the transcriptional response to subsequent resistance exercise. Ten moderately trained men performed ~45 min cycling on one leg followed by 4x7 maximal knee extensions for each leg, 15 min later. Thus, one limb performed aerobic and resistance exercise (AE+RE), while the opposing leg did resistance exercise only (RE). Biopsies were obtained from m. vastus lateralis of each leg 3-h after the resistance exercise bout. Using DNA microarray, we analyzed differences (≥1.5-fold, FDR ≤10%) in gene expression profiles for the two modes of exercise. There were 176 genes up- (127) or down-regulated (49) by AE+RE compared with RE. Among the most significant differentially expressed genes were established markers for muscle growth and oxidative capacity, novel cytokines, transcription factors and microRNAs. The most enriched functional categories were those linked to carbohydrate metabolism and transcriptional regulation. Upstream analysis revealed that VEGF, CREB, TET2 and mTOR were regulators highly activated by AE+RE, whereas JnK, Nfβ, MAPK and several miRNA's were inhibited. Thus, aerobic exercise alters the skeletal muscle transcriptional signature of resistance exercise to initiate important gene programs promoting both myofiber growth and improved oxidative capacity. These results provide novel insight into human muscle adaptations to diverse exercise modes and offer the very first genomic basis explaining how aerobic exercise may augment, rather than compromise muscle growth induced by resistance exercise.