Leucine is an essential nutrient with potent abilities to stimulate both muscle protein synthesis as well as increased oxidative metabolism supported by mitochondrial biogenesis. Few studies have simultaneously investigated anabolic and catabolic responses following leucine treatment with the exception of master regulator of cellular energetics, AMPK. The unique ability of leucine to stimulate both favorable anabolic and catabolic processes in highly metabolically active tissues suggests leucine consumption/supplementation may provide benefits beyond hypertrophic gains. This review highlights original investigations reporting leucine’s ability to stimulate both anabolic and catabolic processes in muscle. Additionally, this report discusses potential explanations for the simultaneous activation of two seemingly opposing processes, as well as the interplay between them. The role of cellular energetics is of undeniable importance in sustaining increased protein synthesis following leucine administration; however, the dependence of leucine-induced mitochondrial biogenesis on heightened energy expenditure from elevated protein synthesis remains to be defined experimentally.