BACKGROUND The diagnosis of the site of origin of metastatic neoplasms often poses a challenge to practicing pathologists. A variety of immunohistochemical and molecular tests have been proposed for the identification of tumor site of origin, but these methods are no substitute for careful attention to the pathologic features of tumors and their correlation with imaging findings and other clinical data. The current trend in anatomic pathology is to overly rely on immunohistochemical and molecular tests to identify the site of origin of metastatic neoplasms, but this "shotgun approach" is often costly and can result in contradictory and even erroneous conclusions about the site of origin of a metastatic neoplasm. OBJECTIVE To describe the use of a systematic approach to the evaluation of metastatic neoplasms. METHODS Literature review and personal experience. CONCLUSIONS A systematic approach can frequently help to narrow down differential diagnoses for a patient to a few likely tumor sites of origin that can be confirmed or excluded with the use of selected immunohistochemistry and/or molecular tests. This approach involves the qualitative evaluation of the "pretest and posttest probabilities" of various diagnoses before the immunohistochemical and molecular tests are ordered. Pretest probabilities are qualitatively estimated for each individual by taking into consideration the patient's age, sex, clinical history, imaging findings, and location of the metastases. This estimate is further narrowed by qualitatively evaluating, through careful observation of a variety of gross pathology and histopathologic features, the posttest probabilities of the most likely tumor sites of origin. Multiple examples of the use of this systematic approach for the evaluation of metastatic lesions are discussed.