Multitarget-directed ligands (MTDLs), an emerging and appealing drug discovery strategy, utilizing a single
chemical entity to inhibit multitargets, was confirmed to be effective in reducing the likelihood of drug resistance, diminishing
problems of dosing complexity, drug-drug interactions and toxicities, as well as improving patient compliance. The
exploration of MTDL strategy should be valuable in anti-HIV drug discovery. In this article, current knowledge and
strategies for the rational design of the multitarget and selective anti-HIV agents are described and a number of illustrative
examples are given. Moreover, the challenges, limitations and outlook of such novel drug design strategies are also presented,
with a goal to highlight the representative paradigms in the rational design of MTDLs, and to help medicinal
chemists discover the next generation of multitarget anti-HIV agents.