Access to effective antimalarial therapy has increased dramatically. As malaria-endemic countries begin to use artemisinin-based combination therapy (ACT) to treat malaria, detecting the emergence and spread of resistance has become more complicated but also more urgent. Clinical efficacy studies may not be sensitive enough to detect the failure of a single component of combination therapy while standardized criteria for in vitro resistance and validated molecular markers are not yet available to many currently deployed drugs. This review discusses the challenges to various methods to monitor antimalarial drug resistance and proposes an integrated approach to the rapid detection and characterization of resistance to ACTs should it arise.