Chloroquine-resistant malaria is a major public health threat in sub-Saharan Africa. While a few countries have already replaced chloroquine as the first-line therapy for uncomplicated malaria or are in the process of doing so, other countries are faced with the complicated task of assessing the current status of drug resistance, making national policy-level decisions about whether to replace chloroquine or not, and initiating a monitoring system to track changes in the efficacy of malaria therapy. There is currently no standardized approach for collecting and interpreting data on therapy efficacy. There is also no agreement as to how much chloroquine resistance or treatment failure is acceptable and how much warrants a change in treatment policy. Using data collected in 10 sites in eastern and southern Africa between 1990 and 1996, we have assessed the therapeutic response to chloroquine and investigated predictors of clinical success or failure. Based on these experiences and analyses, a standardized protocol for in vivo studies of the efficacy of malaria therapy and for approaches to designing monitoring systems are proposed. The process of making policy-level decisions based on data collected by these systems is also discussed.