BCAAs are not synthesized in the body in humans, but they are crucial in protein and neurotransmitter synthesis. The protein anabolic role of BCAAs seems to be mediated not only by their important role as a promoter of the translation process (and possibly acting at the transcription level) but also by inhibition of protein degradation. Leucine may play a critical role in these signaling pathways. Supplementation with BCAAs spares lean body mass during weight loss, promotes wound healing, may decrease muscle wasting with aging, and may have beneficial effects in renal and liver disease. BCAA supplementation is extensively used in the athletic field with the assumption of improved performance and muscle mass. Measuring serum BCAAs has limited clinical utility beyond the controlled setting because levels are affected by a variety of clinical states, and optimal levels in these scenarios have not been completely elucidated. We discuss the effects diet, hormones, stress, aging, and renal or liver dysfunction have on BCAA levels and how understanding the biological effects of BCAAs may help to develop biomarkers of BCAA status. We also discuss potential biomarkers of BCAA status.