Humans respond differently toward exposure against pathogens and some individuals are completely resistant against transmission due to a genetically determined susceptibility. A rising number of such, so-called, host factors have been described during the last years, but their role for diagnostic or therapeutic application is still to be clarified. Here, we describe the biology of the chemokine receptor CCR5 and its polymorphism in the context of host adaptation and immune system function. Furthermore, the first clinical applications exploiting our knowledge of this chemokine receptor as a host factor are described.