Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in prostate cancer. Radiolabeled small molecules that bind with high affinity to its active extracellular center have emerged as a potential new diagnostic standard of reference for prostate cancer, resulting in images with extraordinary tumor-to-background contrast. Currently, gallium 68 (68Ga)-PSMA-11 (or HBED-PSMA) is the most widely used radiotracer for PSMA positron emission tomography (PET)/computed tomography (CT) or PSMA PET/magnetic resonance (MR) imaging. Evolving evidence demonstrates superior sensitivity and specificity of PSMA PET compared to conventional imaging, with frequent identification of subcentimeter prostate cancer lesions. PSMA PET is effective for imaging disease in the prostate, lymph nodes, soft tissue, and bone in a "one-stop-shop" examination. There is emerging evidence for its clinical value in staging of high-risk primary prostate cancer and localization of disease in biochemical recurrence. The high sensitivity provided by PSMA PET, with frequent identification of small-volume disease, is redefining patterns of disease spread compared with those seen at conventional imaging. In metastatic castration-resistant prostate cancer, PSMA PET is frequently used for theranostic selection (eg, lutetium 177-PSMA radionuclide therapy), but its potential use for therapy monitoring is still under debate. However, evidence on its proper use to improve patient-related outcomes, particularly in the setting of early biochemical recurrence and targeted treatment of oligometastatic disease, is still missing. Despite the term prostate specific, PSMA functions as a folate hydrolase and is expressed in a range of normal tissues and in other benign and malignant processes. Knowledge of its physiologic distribution and other causes of uptake is essential to minimize false-positive imaging findings. ©RSNA, 2018.