The past decade has seen many exciting achievements and advances in the treatment of HIV infection. One of the key components in this ever-evolving remedial strategy has been medicinally efficacious enzymatic inhibitors targeting the essential viral aspartyl protease. While the use of currently approved HIV protease inhibitors in concert with drugs that target the reverse transcriptase has dramatically ameliorated the disease state for many individuals, highly-structured dosing regimens accompanied by adverse side-effect profiles have led to a significant level of patient non-compliance. In addition, the development of and selection for resistant mutants have limited the long-term therapeutic outlook of the current protease inhibitors. The need for complementary agents in this salutary class addressing these challenges and opportunities is vividly clear. To this end, much attention and focus has been placed on cyclic, non-peptidic protease inhibitors, exemplified by dihydropyrones and ureas, and their possible future role in this medicinal campaign. The strategies to their design as well as their biological, pharmacokinetic and resistance profiles, and their clinical application will be discussed.