Human immunodeficiency virus (HIV) therapy has evolved over the last 20 years from mono-drug therapy given five times daily to regimens consisting of three or four drugs combined in a single-tablet dosed once daily. To allow once-daily administration, several drugs require pharmacokinetic boosting by a concomitantly administered P-glycoprotein and cytochrome P450 inhibitor such as ritonavir. The availability of cobicistat provides an alternative to ritonavir to those who are intolerant to this drug, and the opportunity for co-formulated single-tablet regimens consisting of tenofovir/emtricitabine, cobicistat and elvitegravir, atazanavir or darunavir. The cobicistat/elvitegravir-based regimen is well tolerated and patients achieved high rates of HIV RNA suppression in clinical trials. Cobicistat inhibits renal tubular secretion of creatinine, resulting in increased serum creatinine concentrations and reduced estimated glomerular filtration rate, with a new set point reached after 4 weeks. Treatment limiting renal toxicity with cobicistat/elvitegravir and tenofovir disoproxil fumarate is infrequent and may be further reduced when cobicistat is co-formulated with tenofovir alafenamide fumarate, a novel formation of tenofovir currently undergoing clinical trials.