Resistance is the inherent capacity of a living being to resist untoward circumstances (disease, malnutrition or toxic agents). Resistance has developed to nearly all specific and effective antiviral agents, including all drugs against human immunodeficiency virus (HIV). Resistance develops rapidly when viral replication is not maximally suppressed. Drug-resistant viruses may be transmitted at the moment of primary infection. Assays to measure drug resistance are available in specialized laboratories and warnings are related to possible expanded use of these assays in the absence of randomized studies with prolonged clinical endpoints. Randomized clinical trials to allow general recommendations for the use of resistance assays in clinical practice are still urgently required.