Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms with distinct biological behaviors, depending on the site of origin and the degree of tumor proliferation. Although advances in biochemical and radiological modalities have enhanced the ability to detect NETs, tissue diagnosis remains the gold standard to assess tumor characteristics for treatment decision making. In an era with growing demands for precision diagnostics based on smaller tissue samples, immunohistochemistry has become an indispensable tool in the pathologist's repertoire. In conjunction with clinical findings and cytomorphology, complementary use of 1) markers of neuroendocrine differentiation, 2) markers confirming epithelial nature, 3) markers of cellular proliferation, 4) transcription factors and hormonal markers, as well as 5) predictive and prognostic markers may be necessary to guide patient management in NETs. The current review summarizes common applications of these immunohistochemical markers when confronted with a potential neuroendocrine neoplasm, and proposes a stepwise algorithmic approach to avoid diagnostic errors in targeted biopsies. Cancer Cytopathol 2016;124:871-884. © 2016 American Cancer Society.