Optimal utilization of sentinel node biopsy in the care of cancer patients requires cooperation between the radiologist, surgeon, and the pathologist. Accurate pathologic diagnosis of the sentinel node is central to correct staging, optimal treatment decisions, and precise prognostication of patients with melanoma, breast, colorectal, lung, and gastric cancer. Intraoperative handling, gross dissection, and histologic/immunohistochemical evaluation techniques are all key components of this process. Although not currently part of routine handling, newer molecular techniques may potentially add to the valuable information gained from evaluating sentinel node specimens.