The opioid system is activated in heart failure, which may be cardioprotective but may also be counter-regulatory. Recently, systemic proenkephalin activation has been investigated in various conditions predicting mortality and kidney injury. In acute heart failure, proenkephalin independently predicts mortality and heart failure rehospitalization in addition to traditional risk markers. It also predicts worsening renal function, increasingly recognized as an important risk predictor for poor outcome in heart failure. This article explores the role of enkephalins and delta-opioid receptors in the heart, then reviews studies measuring proenkephalin levels in the circulation and their associations with prognosis.