A complex network of peptide hormones secreted from the gut, adipose tissue, the brain, and other tissues regulate energy balance. Intensive investigation has uncovered the role of many of the major players in energy balance. However, many of these peptide hormones are derived from precursor proteins whose in vivo processing have not been fully studied. In this review we highlight the importance of fully understanding the processing of prohormones and highlight a particular case of why this is important with the recent discovery of the peptide obestatin.