A controversy has arisen over the past several years about the true origin of the human MDA-MB-435 cell line. Originally described as a human breast cancer cell line, subsequent expression array studies instead suggested a gene expression profile consistent with a melanoma origin. Subsequent karyotype and comparative genomic hybridization studies supported the idea that current stocks of both MDA-MB-435 cells and M14 melanoma cells must be identical cell lines, and the conclusion was drawn that both cell lines were in fact M14 melanoma cells. However, an alternate conclusion based on these data is that both cell lines are indeed identical, but are in fact MDA-MB-435 breast cancer cells. There is evidence that many cell lines can display “lineage infidelity” and that assignment to tissue type is unreliably made based on expression patterns. Evidence from the literature is presented here that is inconsistent with both lines being of M14 melanoma origin, but rather is consistent with both cell lines being of MDA-MB-435 breast cancer origin. [Cancer Res 2009;69(13):5292–3]