Long-term treatment of HIV-1-infected patients with antiretroviral agents may result in failure of therapy, due to the rapid emergence of resistant virus mutants with decreased susceptibility to therapeutic agents. However, in addition to viral resistance other factors, i.e. cellular factors, may contribute to the waning efficiency of chemotherapy. It has been shown in vitro that continuous treatment of cell lines with nucleoside reverse transcriptase inhibitors, such as 3'-azido-2',3'-dideoxythymidine (zidovudine, AZT), may induce decreased activity of cellular thymidine kinase (TK). Measurements of TK activity in ex vivo stimulated peripheral blood mononuclear cells of HIV-1-infected patients who undergo AZT long-term monotherapy as well as combination therapy provide evidence that diminished cellular TK activity may develop. This leads to the assumption that due to long-term treatment with nucleoside analogs, altered drug metabolism in host cells may contribute to inefficient activation of chemotherapeutic agents in HIV-1 patients. Thus, intracellular subtherapeutic levels of the active compounds may develop. In this intracellular environment, selection of resistant virus populations may be promoted. Due to the expanding number of antiretroviral compounds and the requirement for lifelong treatment of HIV-1-infected persons with antiretroviral agents, both viral and cellular resistance mechanisms must be considered in the context of failing chemotherapy.