Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) is increasingly being used worldwide as part of the clinical workup for men with prostate cancer. With high overall accuracy for the detection of prostate cancer, PSMA-targeted PET has an increasingly established role in the setting of biochemical failure after primary therapy and an evolving role in the setting of initial disease staging; its utility for guiding management in the setting of metastatic disease is less clear. Although the specificity is high, familiarization with potential pitfalls in the interpretation of PSMA-targeted PET, including knowledge of the causes for false-positive and negative examinations, is critical. The aim of this best practice report is to provide an illustrative discussion of the current and evolving clinical indications for PSMA-targeted PET, as well as a review of physiological radiopharmaceutical biodistribution and potential imaging pitfalls.