HAART has increased the life expectancy of HIV-infected individuals significantly. Optimal adherence to HAART results in viral suppression and immune recovery in the majority of HIV-infected persons. Data from the early HAART era suggest that adherence levels of greater than 95% are necessary to achieve and maintain virological suppression. However, the optimal threshold of adherence required to maximize the pharmacological benefits of contemporary antiretroviral regimens, particularly in the virologically suppressed patient, is unknown. This review examines new data on the role of adherence in the late HAART era, focusing on virological, immunological and epidemiological aspects. We begin with a discussion of the impact of adherence on viral dynamics and immunological parameters in the virologically suppressed patient. We then review the importance of adherence in emerging antiretroviral treatment strategies. Finally, we summarize accumulating data on the role of antiretroviral adherence in the prevention of HIV transmission. Taken together, the data reviewed reinforce the critical importance of adherence in the management of HIV infection in the late HAART era.