Artemisinin-based combination therapies (ACTs) are the primary treatment for Plasmodium falciparum malaria. However, the emergence of parasites with reduced susceptibility to artemisinin, a phenomenon often observed as delayed parasite clearance, presents a challenge to malaria control. Mutations in the kelch13 (PfK13) gene are considered a key molecular marker for this resistance. Certain PfK13 mutations, including C580Y and R539T, have been correlated with reduced susceptibility in vitro and in vivo. The resistance mechanism appears to involve contributions from other genetic factors related to processes such as endocytosis and phosphatidylinositol metabolism. Genomic surveillance has documented the spread of these mutations, showing established prevalence in Southeast Asia and independent emergences in Africa. Monitoring these variants through molecular surveillance is a critical component of efforts to track resistance patterns. Integrating genomic data with clinical efficacy studies can help inform public health strategies aimed at preserving ACT utility. Future research should focus on functionally validating new mutations and enhancing surveillance capabilities in endemic regions.