Since the advent of combined antiretroviral therapy there have been reductions in mortality and morbidity from HIV, transforming the disease into a chronic medical condition where newly diagnosed individuals can expect to live a near-normal life expectancy. When choosing therapy, probably the most important consideration is the risk of developing drug-related toxicity both in the short and long term, and new strategies to permit individualization of therapy will play a vital role in reducing this risk. The management of comorbidities including cardiovascular, renal, hepatic, bone and CNS disease, coinfections and malignancy are important considerations when choosing combined antiretroviral therapy, as is the cost of therapy. In individuals failing therapy, treatment switches will be guided by the presence of present and previously detected resistance mutations. This article will focus on the evidence for current therapies and strategies in ART-naive individuals and the potential for use of novel agents in the future.