Highly-active antiretroviral (ARV) therapy (HAART) has lead to a sharp decline in AIDS-related morbidity and mortality. Treatment failure is a common, significant problem and as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV therapy. Clinicians must be knowledgeable about the reasons for treatment failure and the best options available for management. Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma concentration and drug resistance. Strategies used when selecting salvage therapy include the use of resistance testing to choose a regimen, the exploitation of pharmacokinetic interactions by boosting protease inhibitor (PI) trough levels and counselling the patient on compliance. When selecting the agents to use in salvage therapy, the new regimen should ideally include as many new agents to which no or minimal resistance is anticipated and at least one new class of drugs if possible. Data on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens based on what is anticipated about cross-resistance and drug interactions. It is important that new agents and new targets continue to be developed as an increasing number of patients in practice have exhausted all treatment options.