Testing for alterations in HER-2/neu in breast cancer has become increasingly popular in recent years, particularly with the recent development of a humanized antiHER-2/neu monoclonal antibody, trastuzumab, which is currently being employed in conjunction with cytotoxic chemotherapy to treat metastatic breast cancer in patients whose tumors exhibit this HER-2/neu alteration. Controversy exists not only on the optimal method of laboratory testing for this HER-2/neu alteration (i.e., fluorescence in situ hybridization (FISH) versus immunohistochemistry (IHC) versus others), but also on the type of reagents used for a given method. A plethora of published studies on tissue-based HER-2/neu testing has recently appeared in many peer-reviewed journals; many have concluded that IHC could be used as a first-line screening test, with the recommendation of FISH to confirm indeterminate results. In contrast to these studies, a recent study by Pauletti et al. showed that HER-2/neu testing by IHC does not predict clinical outcome as accurately as does FISH. This commentary discusses the findings of this study, within a broader review of critical issues relating to HER-2/neu testing in breast cancer.