Assessment of kidney function is primarily based on urine output and Creatinine (Cr)-based methods to estimate glomerular filtration rate (GFR). The latter is confounded as Cr is not exclusively filtered by the kidney and rises relatively late after the onset of acute kidney injury (AKI). This leads to delays in recognition of reduced kidney function and diagnosis of AKI, particularly in critically ill patients where kidney function can change rapidly. The gold standard methods of GFR determination, such as inulin or iohexol clearance, are labor intensive and unfeasible in acute clinical settings. Proenkephalin A 119-159 (PENK) has been intensively studied as a novel biomarker of kidney function. PENK belongs to the enkephalin peptide family and is freely filtrated in the glomerulus. Plasma PENK concentration appears to correlate strongly with GFR. Moreover, increased plasma PENK concentrations are found to be associated with long-term kidney outcomes and mortality. In this review, we summarize the role of PENK in assessment of kidney function and its capacity to predict various clinical outcomes.