Treatment failure due to the rise of drug-resistant viral strains remains a serious problem confronting HIV treaters and patients alike. Among patients receiving antiretroviral therapy for HIV infection, new mutations associated with drug resistance continue to emerge, as do new patterns of cross-resistance and multidrug resistance. Drug-resistant HIV variants are now becoming so widespread that an increasing number of patients are experiencing "primary" resistance, having been infected with drug-resistant and sometimes multidrug-resistant strains. Drug-specific resistance mutations, in some cases, show resistance to a number of anti-retroviral drugs in the same class. Recent data have shown that there is more cross-resistance among the nucleoside reverse transcriptase inhibitors than initially thought. The growing complexity of the HIV-1 resistance spectrum calls for more sophisticated testing and clinical expertise, in addition to more effective drugs.