Plasmodium falciparum resistance against artemisinin has not emerged in Africa; however, there are reports of the presence of polymerase chain reaction-determined residual submicroscopic parasitaemia detected on day 3 after artemisinin-based combination therapy (ACT). These residual submicroscopic parasites are thought to represent tolerant/resistant parasites against artemisinin, the fast-acting component of the combination. This review focused on residual submicroscopic parasitaemia, what it represents, and its significance on the emergence and spread of artemisinin resistance in Africa. Presence of residual submicroscopic parasitemia on day 3 after treatment initiation leaves question on whether successful treatment is attained with ACT. Thus there is a need to determine the potential public health implication of the PCR-determined residual submicroscopic parasitaemia observed on day 3 after ACT. Robust techniques, such as in vitro cultivation, should be used to evaluate if the residual submicroscopic parasites detected on day 3 after ACT are viable asexual parasites, or gametocytes, or the DNA of the dead parasites waiting to be cleared from the circulation. Such techniques would also evaluate the transmissibility of these residual parasites.