  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 the 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-year 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 the 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 the nucleus. In
conclusion, the key site of CQ action may be in the 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.
