Maximizing metabolic stress at a given level of mechanical stress can improve the adaptive response to endurance training, decrease injury, and potentially improve performance. Calcium and metabolic stress, in the form of heat, decreases in the adenosine triphosphate/adenosine diphosphate ratio, glycogen depletion, caloric restriction, and oxidative stress, are the primary determinants of the adaptation to training. These stressors increase the activity and amount of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a protein that can directly induce the primary adaptive responses to endurance exercise: mitochondrial biogenesis, angiogenesis, and increases in fat oxidation. The activity of PGC-1α is regulated by its charge (phosphorylation and acetylation), whereas its transcription is regulated by proteins that bind to myocyte enhancing factor 2, enhancer box, and cyclic adenosine monophosphate response element sites within the PGC-1α promoter. This brief review will describe what is known about the control of PGC-1α by these metabolic stressors. As the duration of calcium release and the amount of metabolic stress, and therefore the activation of PGC-1α, can be directly modulated by training and nutrition, a simple strategy can be generated to maximize the adaptive response to endurance training.