Inhibition of HIV entry by blocking co-receptors may be a new target for antiretroviral treatment. Among the co-receptors CCR5 is the most attractive one to focus on, since the majority of HIV strains uses this molecule for cell entry. Furthermore, there is biological evidence from subjects with a mutation in the CCR5 gene that blocking CCR5 may not cause immunological or other damage in patients. Three CCR5 antagonists (maraviroc, aplaviroc and vicriviroc) have been tested in patients so far. The clinical development of aplaviroc had to be stopped due to the occurrence of hepatotoxicity. Both maraviroc (MVC) and vicriviroc (VCV) have shown substantial antiviral activity in short-term monotherapy studies and were not associated with severe adverse effects. Studies in treatment- naïve and experienced patients have been performed or are currently underway, respectively. Vicriviroc in combination with AZT and 3TC failed to demonstrate non-inferiority when compared to standard therapy with efavirenz , AZT and 3TC in treatment- naïve subjects. A substantial proportion of patients treated with VCV failed virologically and developed resistance mutations to 3TC. In contrast, a recent study in heavily pretreated patients with CCR5- tropic virus showed superiority of ritonavir boosted VCV plus optimized background therapy (OBT) as compared to OBT pus placebo. These data indicate that VCV may be a therapeutic option for patients. However, the optimal dose and the patient population to be treated have still to be defined by further studies. While development of resistance to CCR5 antagonists has not been observed in patients so far, presence of X4 virus at baseline or tropism shift from CCR5 to CXCR4 may be an explanation for treatment failure. Both causes have been observed in clinical studies. This underlines the need of performing a highly sensitive tropism assay before introdcuing a CCR5 inhibitor. A clinical study with MVC in patients with dual tropic virus showed no additional antiviral effect of MVC to OBT after 24 weeks. On the other hand, this study does not indicate that blocking of CCR5 in patients with R5/X4 virus is harmful in terms of CD4 cell- decline or clinical deterioration. In summary, there is growing evidence from clinical studies that CCR5 antagonists may play an important role as antiretroviral agents in the future. Sensitive assays for the exclusion of X4 virus seem to be crucial for a successful clinical use of these drugs.