Performance of striated muscle relies on the nerve-driven activation of the sarcomeric motor and coupled energy supply lines. This biological engine is unique; its mechanical and metabolic characteristics are not fixed, but are tailored by functional demand with exercise. This remodelling is specific for the imposed muscle stimulus. This is illustrated by the increase in local oxidative capacity with highly repetitive endurance training vs. the preferential initiation of sarcomerogenesis with strength training regimes, where high-loading increments are imposed. The application of molecular biology has provided unprecedented insight into the pathways that govern muscle plasticity. Time-course analysis indicates that the adjustments to muscle work involve a broad regulation of transcript expression during the recovery phase from a single bout of exercise. Highly resolving microarray analysis demonstrates that the specificity of an endurance-exercise stimulus is reflected by the signature of the transcriptome response after muscle work. A quantitative match in mitochondrial transcript adjustments and mitochondrial volume density after endurance training suggests that the gradual accumulation of expressional microadaptations underlies the promotion of fatigue resistance with training. This regulation is distinguished from control of muscle growth via the load-dependent activation of sarcomerogenesis. Discrete biochemical signalling systems have evolved that sense metabolic perturbations during exercise and trigger a specific expression program, which instructs the remodelling of muscle makeup. A drop in muscle oxygen tension and metabolite perturbations with exercise are recognized as important signals in the genome-mediated remodelling of the metabolic muscle phenotype in humans.