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SN biopsy (SNB) has evolved rapidly during the past decade and has now become a standard of surgical care for patients with breast cancer. The primary purpose of SNB is to minimize patient morbidity from axillary staging, but SNB also presents research opportunities to further understand the role of the sentinel node in the natural history of breast cancer. We have attempted to highlight several issues regarding SN and its biopsy in this review, including:(1) Investigation of the optimal particle size for radiotracers. The success of SNB is, in large part, attributed to the particle size of radiolabeled tracers. Electron microscopy demonstrated significant accumulation of the tracer (tin colloid) in harvested SN, of which particle sizes were in the range of 100-150 nm. Therefore, this appeared to be a suitable particle size for SN identification. (2) Invention of a new gamma probe. A cord-and boxless handheld gamma probe was invented, which was more sensitive to radioactivity and involved a background subtraction function based on defined criteria. (3) Characterization of the immunologic response against tumor antigens. Fluorescence-activated cell sorting (FACS) analyses were performed to determine the phenotypic characteristics of B cells and T cells in SN. They revealed an increase in B cells expressing co-stimulated molecules as antigen-presenting cells in SN, compared with non-SN. With respect to T cells, a heterogeneous pattern of naive and memory T cells (TCM) was demonstrated in SN, in contrast to homogeneous pattern with TCM in non-SN. These results may support the concept that B cells play a significant role in antigen presentation required for T cell activation. Studies are currently in progress to test these possibilities.