Virologic relapse after initial virologic suppression remains a concern for patients on antiretroviral therapy (ART). Multiple factors may contribute to virologic relapse, including suboptimal adherence, resistance, and pharmacokinetic issues. The major guidelines for HIV care are in agreement that ART regimen change is indicated in relapse because resistance is identified, but the guidelines are not completely clear on the timing of regimen change. When relapse occurs due to resistance, patients may continue with viremia well below their set points, stable or increasing CD4+ counts, and clinical health for several years. However, delaying a switch in the treatment regimen may lead to the accumulation of resistance which compromises future treatment response. In general, a lower switch threshold is recommended for patients during relapse on first or second line regimens.