|Highly active antiretroviral therapy (HAART) is the current standard of care for human immunodeficiency virus (HIV) infections. Although drug resistance may have been present before the introduction of antiretroviral (ARV) therapy due to random genetic variation, the introduction of ARV therapy exerts selective pressure over viral subpopulations to develop resistance. The use of HAART decreases the risk of resistance when compared with mono or dual therapy regimens. However, drug resistance remains an undesirable outcome of long-term therapy. Understanding and applying general principles in the proper use of ARV therapy will lessen drug resistance. While initially patients and clinicians have multiple regimens available to them, challenging situations arise when patients develop adverse reactions, intolerance, and decreased adherence and are choosing a new regimen to replace a failing one.