The N-end rule finds a physiological function The N-end–rule pathway for protein degradation is a canonical degradation pathway discovered in the 1980s. In recent years, studies have focused on finding novel variant pathways of N-end recognition. The “classical” pathway is blocked by N-terminal acetylation of the substrate. However, in yeast, N-terminal acetylation need not block degradation, because a second pathway can act on acetylated N-termini. But is this alternate pathway a major player in the physiology of mammals? Park et al. now confirm the existence of the alternate pathway in mammalian cells. Most notably, patient-derived point mutations thought to confer hypertension in humans affect susceptibility to this pathway for the encoded protein substrate, Rgs2. Science , this issue p. 1249