Differential diagnosis of endocrine neoplasms as benign or malignant is frequently extremely difficult. Similarly, assessing prognosis in cases of malignancy is problematic. Traditionally, histologic criteria, including grade of the tumor, architectural features, and cytologic appearance, have been used to predict biologic behavior. In addition, clinical scoring systems may be useful in assigning prognosis in individual cases. Examination of the DNA profile of individual cells by flow cytometry may correlate with the aggressiveness of the tumor. Recent developments in molecular genetics have yielded genetic markers that may be useful in diagnosis and prognosis as well as illuminating the pathogenesis of endocrine neoplasia. This review summarizes the status of traditional and newer methods of pathologic interpretation of endocrine neoplasms. In general, the most accurate assessment of these tumors is derived from consideration of a collage of the clinical and pathologic criteria discussed herein.