Resistance testing should be readily available to every clinician who specializes in HIV/AIDS. Based in part on requests we receive in our laboratory, we believe that the use of resistance testing is expanding. However, selecting an initial antiretroviral treatment regimen or changing a failing one according to the test results is complex and inexact and requires knowledgeable interpretation to maximize the clinical benefit. Future studies about viral fitness and other viral, host, and pharmacologic factors responsible for disease progression likely will facilitate more precise application of resistance testing to the clinical setting.