Human immunodeficiency virus (HIV) infections are characterized by a high degree of viral variation. The genetic variation is thought to be a combined effect of a high error rate of reverse transcriptase (RT), viral genomic recombination, the selection forces of the human immune system, the requirement for growth in multiple cell types during pathogenesis, and persistent immune activation associated with HIV disease. This hypermutability gives the virus an ability to escape mechanisms of innate immune surveillance and therapeutic interventions. Indeed, HIV variants that are resistant to drugs that antagonize both the HIV protease and RT enzymes are well described. Furthermore, there are seemingly no procedures to restrict this disarming property of HIV to mutate rapidly. Recently we have shown that some of the drug-resistant RTs display an increased in vitro polymerase fidelity. The question is whether this finding will stimulate new approaches that will not only help the immune system to deal with the virus more efficiently but also to reduce or delay resistance to various classes of anti-HIV drugs. The pros and cons of this concept and the influence of viral replication rates and viral fitness on HIV variability are discussed.