The discovery of highly divergent strains of human immunodeficiency virus (HIV) not reliably detected by a number of commonly used diagnostic tests has underscored the need for effective surveillance to track HIV variants and to direct research and prevention activities. Pathogens such as HIV that mutate extensively present significant challenges to effective monitoring of pathogens and to disease control. To date, relatively few systematic large-scale attempts have been made to characterize and sequence HIV isolates. For most of the world, including the United States, information on the distribution of HIV strains among different population groups is limited. We describe herein the implications resulting from the rapid evolution of HIV and the need for systematic surveillance integrated with laboratory science and applied research. General surveillance guidelines are provided to assist in identifying population groups for screening, in applying descriptive epidemiology and systematic sampling, and in developing and evaluating efficient laboratory testing algorithms. Timely reporting and dissemination of data is also an important element of surveillance efforts. Ultimately, the success of global surveillance network depends on collaboration and on coordination of clinical, laboratory, and epidemiologic efforts.