Resistance to artemisinin derivatives (ARTs) in malaria disease is currently defined as a delayed parasite clearance following artemisinin combined therapy (ACT). Although ACT is still widely effective, the first evidence of artemisinin resistance was described in 2009 in Southeast Asia. Since then, resistance to ARTs / ACT has been monitored showing an increasing trend. The demonstrated resistance to all drugs that are currently associated to ART, the ambiguous finding that ART resistance is observed only in presence of resistance to the partner drug, the lack of a mechanistic rationale to choose the partner drugs and the lack of markers with known specificity and sensitivity to monitor ART resistance, represent the most worrisome issues.