Both CD4 cell counts and measurements of plasma HIV-1 RNA (i.e. viral load) have become established surrogate markers for predicting treatment and disease outcome in HIV infection, and are instrumental for the evaluation of new antiretroviral drugs in clinical trials. Recently, HIV drug-resistance testing has also become available and has been shown to have prognostic value in providing guidance with antiretroviral therapy. The identification of robust surrogate markers is also an essential requirement for the clinical development of targeted anticancer agents, which unlike their cytotoxic counterparts, are often devoid of the toxicities that have been traditionally used to monitor the efficacy of chemotherapy. In particular, biological or molecular markers that are predictive of a drug effect need to be integrated into early efficacy trials of targeted therapies in order to confirm that the drug is in fact “hitting” the intended target. The full clinical significance of many of the altered cell types or polymorphisms, which are selected by cytostatic agents, remains to be elucidated. However, molecular genotyping of these targets, akin to drug resistance testing for HIV infection, may constitute an important strategy to assist with the selection and monitoring of targeted chemotherapy in cancer patients. Thus, lessons from HIV/AIDS on the value of surrogate makers may assist with the development and optimization of targeted cancer therapy.