Successful diagnosis and treatment of primary hyperparathyroidism (pHPT) begin with a systematic approach based on a sound understanding of calcium physiology, application of best contemporary evidence, knowledge of embryology and anatomy, and utilization of imaging and other technology when available and indicated. This chapter will provide the reader with a rubric into which disparate clinical data can be organized in order to confidently achieve or exclude the correct diagnosis of pHPT and direct appropriate treatment for the same.