In 1996, an Ad Hoc Committee on Health Research Relating to Future Intervention Options (formed under the auspices of the World Health Organization) described a model for setting priorities in research funding. This model, however, as presented in the Ad Hoc Committee's report entitled Investing in health research and development, fails in the following important situations: (i) when there is a health problem about which little is known; (ii) when current control measures are unsustainable; (iii) when there are complex risk factors, like "social factors", which affect many different diseases; and (iv) when the disease burden and resources for control vary greatly from one place to another. In situations of uncertainty or complexity, a method of priority-setting that emphasizes certainty and simplicity may actually mislead. A transparent, matrix-based process--illustrated with an example of priority-setting for malaria--may permit such uncertainty and complexity to be better taken into account in setting health research priorities.