Nucleus may be the key site of chloroquine antimalarial action and resistance development.

The first proposed hypothesis about the mechanism of chloroquine (CQ) action on malaria parasites is DNA intercalation hypothesis which indicates that the site of CQ action is within nucleus. Later on the interest of research was shifted from nucleus to lysosome due to the report of CQ accumulation within lysosome. The current opinions about CQ action and resistance are mainly based on the results of more than 30 years' studies on lysosome, which can be used to explain some facts but still remains incomplete and controversial. Based on recently published papers and our related data it is possible that the key CQ target protein may exist in nucleus. Development of CQ resistance is probably mainly due to the alteration in the CQ target protein or certain mechanism which prevents CQ from reaching its target protein in nucleus. In conclusion, the key site of CQ action may be in nucleus though it has not been well explored while CQ action in lysosome which has been well studied may be secondarily important in CQ action and resistance.