Lymphatic mapping with selective sentinel lymphadenectomy allows accurate pathologic examination of the nodes most likely to contain macro- or micrometastastic disease for staging and proper adjuvant chemotherapy. The hypothesis of SLN biopsies was histopathologically validated by Turner et al that if the node is tumor free by H&E and immunohistochemistry, the probability of non-SLN involvement is less than 0.1%. Giuliano et al and Veronesi et al reported that detection of metastases in SLNs by frozen section technique is 89% and 64%, respectively. At MCC, frozen section evaluation of SLN is not performed because of its potential loss of micrometastasis in the cryostat, freezing artifacts, sampling error, and perhaps radioactive contamination. Intraoperative detection of macro- or micrometastasis is critical because it enables conversion of patients with positive SLN to CLND in one surgical setting more cost-effectively. IIC of the lymph nodes has been used routinely in the diagnosis of hematologic malignancies and also in breast cancer as a useful method in many series. In the author's experience, IIC by Diff-Quik stain converted 100% of grossly positive and suspicious SLNs and 22% of grossly negative SLNs. The significance of detecting micrometastases in axillary lymph nodes using immunohistochemical techniques has been reported in many series. At the MCC, routine use of CKI on paraffin sections of grossly negative SLNs enabled the upstaging of 10.6% of patients from N0 to N1. Recent addition of intraoperative rapid CKI as an adjunct to complement Diff-Quik stain has proven to be more sensitive in detecting micrometastases than using Diff-Quik stain alone. IIC technique using either Diff-Quik stain or CKI requires intensive training and experience to avoid potential pitfalls and errors in interpretation. Evaluation of SLN should use methods that enhance the ability to detect micrometastasis, however, in a cost-effective manner. The cost-effectiveness of IIC by Diff-Quik stain is incomparable with frozen section evaluation. The added cost of routine immunohistochemical stain and perhaps multiple levels of H&E stain should be offset by the decreased costs of IIC and clinically by treating most patients in the outpatient settings. In summary, IIC by Diff-Quik stain is simple, rapid, and has excellent diagnostic accuracy in grossly positive and suspicious SLNs allowing cost-effective, immediate CLND. IIC by CKI is an extremely useful ancillary technique that complements Diff-Quik stain in detecting micrometastases particularly in low grade ductal or lobular carcinoma and low tumor cell volume. Appropriate combined use of both stains may lead to intraoperative nodal staging and cost-effective CLND. SLN mapping technology at MCC using IIC in conjunction with serial sections, entire tissue submission, routine use of CKI, and multiple levels of the SLN have led us to uncover micrometastasis in high-risk, traditionally node-negative patients. These results have encouraged investigators to pursue even more sensitive techniques to detect micrometastases, including molecular biology techniques such as RT-PCR. Experienced cytopathologists and active cytopathology services are required to avoid potential pitfalls in performing and interpreting IIC. More long-term follow-up and prospective trials are needed to determine the prognostic significance of upstaging by ancillary techniques, which may lead to a revision of the current TNM staging system.