Preservation of aerobic fitness and skeletal muscle strength through exercise training can ameliorate metabolic dysfunction and prevent chronic disease. These benefits are mediated in part by extensive metabolic and molecular remodeling of skeletal muscle by exercise. Aerobic and resistance exercise represent extremes on the exercise continuum and elicit markedly different training responses that are mediated by a complex interplay between a myriad of signaling pathways coupled to downstream regulators of transcription and translation. Here, we review the metabolic responses and molecular mechanisms that underpin the adaptatation of skeletal muscle to acute exercise and exercise training.