Almost half of the human genome is derived from exogenous genetic invaders, most of them related to retroviruses. This is the consequence of longstanding interactions between retroelements and higher organisms, governed by a delicate equilibrium between virus-based evolutionary forces and control by host defense mechanisms. Insight into these longstanding genetic conflicts is suggesting leads for novel therapeutic strategies to fight HIV infection. In 2001, the Human Genome Organisation (HUGO) and the Human Genome Project (HGP) consortia provided first drafts of the sequence of the human genome. Completed in 2004, this effort opened new avenues for understanding the genetic bases of both physiological and pathological process, hence to move towards a more global comprehension of health and disease. As insights into the content of the human genome were gained, it quickly became apparent that only a fraction, barely two percent, encodes for proteins, which had been traditionally considered as the main executive arms of the cell. More strikingly even, close to 50 percent of human DNA was found to derive from genetic invaders called transposons, most of them retroelements functionally related to the human immunodeficiency virus (HIV). Found in the genomes of all species, transposons are motors of evolution, yet their uncontrolled spread can be fatal to their host organisms. Their presence in higher species thus reflects a delicate equilibrium between occasional permissiveness and tight restriction, through innate immunity mechanisms also engaged in protection against their exogenous viral counterparts.