Within the first few years after the introduction of highly active antiretroviral therapy two facts became evident: the treatment was highly effective and proper compliance was essential to achieve the therapeutic objectives. Recently, the regimens containing these drugs have changed. Complex dosing with a large number of tablets taken three times daily together with dietary restrictions has given way to simpler treatments.The main advances include new formulations and new drugs that allow once-daily dosing, the use of ritonavir to enhance the bioavailability of the protease inhibitors and the coformulation of active ingredients in a single capsule. This review analyzes the impact of these interventions on the therapeutic regimen and it discusses the factors that facilitate and those that hinder optimal adherence to highly active antiviral treatment. Adherence is a complex, multidimensional problem. Simplification of the treatment is an important aspect, but it should be accompanied by other strategies focussed on the patient and the medical team in order to achieve effective long-term antiretroviral therapy in all patients.