Highly active antiretroviral therapy (HAART) delays clinical progression by suppressing viral replication, measured by a substantial reduction in HIV RNA, allowing the immune system to reconstitute, measured in most studies by an increase in CD4 cells. These virologic and immunologic consequences do not occur uniformly among HAART users. Markers of HIV disease stage at the time of HAART initiation are critical determinants of the progression while receiving HAART. In this report, we review studies describing the heterogeneous virologic and immunologic progression after the initiation of HAART, discuss methodologic concerns in the study of the response of biomarkers, and update findings obtained in the Multicenter AIDS Cohort Study, which show that CD4 cell count, history of antiretroviral therapy, and age at the time of initiation are independent determinants of response.