The HIV protease inhibitor (PI) ritonavir is a potent, mechanism-based inhibitor of cytochrome P450 CYP3A4, an enzyme that is responsible for metabolizing most HIV PIs. Ritonavir is therefore able to enhance the effectiveness of PI treatment by reducing the pill burden, simplifying dosing regimens and improving therapy adherence. Ritonavir coadministration improves the pharmacokinetic (PK) profiles of concomitant PIs, and represents a cornerstone of PI-containing regimens. However, ritonavir is associated with undesirable side effects, such as gastrointestinal problems and lipid disturbances. This review summarizes salient features and limitations associated with the use of ritonavir as a PK enhancer, and briefly describes novel PK enhancers that are in development.