Fine-needle aspiration (FNA) and core needle biopsy (CNB) represent 2 of the most common minimally invasive tissue sampling modalities. Although similar in many ways, there are significant differences in the collection, processing, interpretation, and suitability for ancillary testing that exist between FNA and CNB. This review provides a brief overview of the strengths and weaknesses of FNA compared with CNB, as well as an update regarding the landscape of recently published studies that investigate the organ-specific comparative performance metrics of FNA and CNB. A current understanding of the benefits and limitations of FNA and CNB will help the cytopathologist and the clinician alike to select the right procedure for the right patient at the right time. Cancer Cytopathol 2016;124:862-870. © 2016 American Cancer Society.