Therapeutic drug monitoring (TDM) is the process by which a patient's dosing regimen is guided by repeated measures of plasma drug concentrations. An enormous challenge with regard to TDM of antiretroviral drugs (ARV) is that the concentration goals can be moving targets. Well-designed prospective studies demonstrating that prospectively altering ARV doses based on TDM leads to virologic success and increased tolerability are needed. Nevertheless, there are specific clinical instances where this experimental intervention should be considered to potentially reduce toxicity and improve therapeutic outcomes.