Co-trimoxazole prophylaxis in HIV-infected persons is beyond doubt one of the cheapest and most important interventions, next to antiretroviral therapy (ART), to improve survival. However, many questions, ranging from programme coverage and public health impact to individual tolerance and compliance, remain unanswered. Together with the need for more research to identify optimal ART regimens for resource-poor settings, research regarding optimal chemoprophylaxis against opportunistic infections should also remain high on the agenda.