Gene expression profiling of cancer began as a research tool but is rapidly moving towards clinical application. The diagnostic category of diffuse large B-cell lymphoma (DLBCL) can now be viewed as an amalgam of several different diseases that have distinct gene expression profiles, oncogenic mechanisms, and clinical outcomes. Other diagnostic categories such as chronic lymphocytic leukemia (CLL) have a single gene expression signature that distinguishes them from other lymphoid malignancies. Nevertheless, elevated expression of a single gene, ZAP-70, is characteristic of a more aggressive subtype of CLL that may require novel treatment approaches. In mantle cell lymphoma (MCL), a quantitative measurement of gene expression associated with tumor proliferation is a powerful predictor of survival. Ultimately, the molecular diagnosis of these malignancies will identify molecular pathways that can be exploited for therapy. For example, one of the gene expression subgroups of DLBCL, termed activated B-cell like DLBCL, is characterized by constitutive activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway, and interference with this pathway selectively kills these lymphoma cells. The full benefit of gene expression profiling can only be realized if we incorporate this technology into prospective clinical trials.