The functions of the approximately 98% of the human genome that do not encode human cellular proteins remain to be elucidated. Actively replicating endogenous retroviruses entered the human genome millions of years ago and became a stable part of the inherited genetic material, with retroviral elements presently making up approximately 8% of the modern human genome. These viruses subsequently acquired multiple mutations, leading to the widely-held assumption that they are no longer competent to replicate. However, in studying living patients rather than the standard cell lines, we have recently discovered surprising evidence suggesting that in certain patients with HIV-1 infection or cancer HERV-K (HML-2), an endogenous retrovirus that is a relatively recent entrant into the human genome and has been linked to oncogenesis, might still be capable of replication. Replication and transmission of endogenous retroviruses is difficult to prove using standard techniques, however, as these viruses are already present in the genomes of all human cells. Therefore, we have used a newly devised molecular system in which antibiotic resistance serves as a surrogate marker to assess whether we can passage virus in tissue culture and/or from the blood of patients. Preliminary studies indicate that this may well be the case. Proof that endogenous retroviruses can still replicate in modern humans will lead to a paradigm shift in thinking about these viruses, and will suggest a role for them in reshaping individual genomes. In addition, as increased expression of chromosomal endogenous retroviral sequences has been linked to cancer and autoimmunity, these findings will be relevant to understanding the pathogenesis of significant diseases.