The expansion of treatment options for HIV infection over the past two decades has been one of the great accomplishments of contemporary pharmacology, transforming a relentlessly progressive and ultimately fatal disease into a chronic illness with the potential for a near normal life expectancy. Knowledge gained through the development of anti-retroviral drugs has provided the foundation for development of compounds useful for other previously untreatable chronic viral infections. With these successes has come a succession of new and often unanticipated challenges. The management of drug resistance is now a centerpiece of clinical care that has fostered rapid adoption of sophisticated molecular diagnostic tools. Unexpected toxicities have been identified for drugs that were once commonly used and thought to be relatively safe. The range of treatment options is now so large that it is impractical to develop evidenced-based guidance for optimal treatment for all but a few clinical circumstances. The interaction between HIV management and the co-morbidities of an aging population introduces increased complexity to medical decision making. The increased frequency of serious medical conditions that are not traditionally associated with HIV raises new uncertainties about when to begin treatment of HIV. An overview of these issues from the perspective of a practicing clinician will be presented.