Nephrotic syndrome (NS) is a key clinical entity for the internist to recognize and understand. A wide range of infectious, metabolic, malignant, and autoimmune processes drive nephrosis, leading to a syndrome defined by proteinuria, edema, and hypoalbuminemia. NS occurs due to increased permeability to proteins at the level of the glomerulus, which allows for passage of albumin and other proteins into the urine. Proteinuria leads to a cascade of clinical complications characterized by fluid accumulation, kidney inflammation, and dysregulation of coagulation and immunity. In this article, the authors review the clinically important etiologies of NS that should inform an initial clinical evaluation