The PCR-determined submicroscopic parasites are those that are below the detection limit of a standard light microscopy, but can be detected by a much more sensitive tool, the PCR [
44]. Residual PCR-determined submicroscopic malaria parasites include both asexual and sexual parasites remaining days after initiation of anti-malarial treatment. ACT has continued to achieve rapid microscopy-determined parasitological clearance across SSA, with a majority of treated patients being cleared of asexual parasites within 48 h of treatment initiation [
3,
35,
45‐
47]. More precisely, over 90% of patients are being microscopically parasite negative by day 2 and 99% by day 3 post-initiation of ACT [
35,
46,
47]. The PCR on the other hand, has revealed the presence in SSA of
P. falciparum genotypes that are probably more likely to survive ACT at submicroscopic level (Table
1), and probably contribute to an onward transmission and subsequent patient recrudescence [
17,
19‐
21,
48]. Studies in Angola [
20], Kenya [
17], Tanzania [
18,
21], and Uganda [
19] have reported substantial proportions of individuals treated with artemisinin-based combination, with residual submicroscopic parasitaemia between days 3 and 7. Whereas a study in Angola has reported an increase, over time, in the proportion of patients with residual submicroscopic parasitaemia on day 3 [
20], a study in Tanzania reported an increase followed by a decline in the proportion of patients with residual parasitaemia across years of surveillance [
21]. Several submicroscopic parasite subpopulations have also been observed in Tanzania with no known
pfk-
13 resistance-associated mutations, however, they clear as slowly as parasites in Cambodia, which are labeled drug resistant and do harbour the mutations [
43]. Interestingly, these parasites in Tanzania with similar prolonged clearance as those in Cambodia were from a study conducted in 2006 at a time when artemether-lumefantrine was not yet adopted as first-line treatment in Tanzania, and thus were probably naive of the drug [
21,
43]. Nevertheless, after nearly two decades of a wide-scale use of ACT in Africa, the combination therapy has remained efficacious despite the presence of residual submicroscopic parasitaemia on day 3 [
3,
16,
17,
19‐
21]. The questions remaining to be answered are, therefore, what are the factors other than parasite tolerance/resistance that may determine the presence of residual submicroscopic parasitaemia after ACT and whether residual PCR-determined submicroscopic parasitaemia represents viable asexual parasites.