HIV clinical research faces limitations even in research-rich settings. Even though important questions remain unanswered, clinical trials will probably never be conducted that address, prospectively, when treatment is optimally indicated, for example. In resource-constrained settings, large, prospective clinical trials are also unlikely. On the other hand, ones with a more observational design or that compare cohort experiences may well be feasible and able to provide information important in those settings, as well as in regions with abundant financial resources.