There are many considerations for stopping and changing antiretroviral (ARV) therapy in the ARV-experienced individual. Given the potential for possible long-term toxicities and the shift to initiating ARV therapy later, it may be reasonable to stop ARV therapy among asymptomatic patients with high CD4 cell counts and low viral loads and carefully monitor them. Ongoing studies are currently evaluating this strategy. Treatment regimen failure may be due to problems with tolerability, adherence, pharmacokinetic issues, or emergence of resistance. Clinicians can utilize two types of resistance testing—genotype and phenotype assays. Generally, continuation of an optimized regimen in the patient with a multidrug resistant (MDR) virus is the best strategy. Structured treatment interruption among patients with an MDR virus is not recommended. New drugs, either recently licensed, such as enfuvirtide, or under investigation, may offer hope to patients with an MDR virus.