Careful laboratory evaluation of sentinel nodes (SNs) is critical to determine the presence of tumor. This requires evaluation of multiple full-face sections from the SN, using H&E staining and immunohistochemistry. In the future, molecular and genetic approaches may be adjunctive to microscopy. Number of tumor-positive SNs and the amount and location of tumor in SNs correlate with tumor spread to non-sentinel nodes, subsequent recurrences and melanoma death, permitting patient assignment to a risk category. J. Surg. Oncol. 2011; 104:369–378. © 2011 Wiley-Liss, Inc.