The human immunodeficiency virus type 1 (HIV-1) pandemic is currently in its third decade and approximately 35 million people are infected worldwide. HIV-1 genetic variability results in 9 phylogenetic subtypes and several circulating recombinant forms (CRFs). In Italy, the first phase of the HIV epidemic was mainly confined to the intravenous drug users (IDU) risk group, moreover most studies have focused on different aspects of the non B subtype such as drugs and therapeutic protocols, laboratory methodologies (heteroduplex mobility assay, PCR screening methods) for the identification of phenotypic variants. These studies were mostly locally conducted. In this context, the Red Queen Hypothesis might be suggestive. In the first original expression that comes from Chapter 2, Through the Looking Glass. To improve our knowledge, in the near future, we will need to investigate the demographic and spatiotemporal history of different HIV-1 subtypes circulating in Italy in a large data set of sequences, involving a sample size comparable with the Italian population. To monitor the genetic evolution of the HIV-1 in a large data-set represent an essential strategy to control the local as well as the global HIV-1 epidemic and to develop efficient preventive and therapeutic strategies, with a great impact in clinical practice.