The mechanisms whereby the intrinsic pruritogenic effect of chloroquine (a property also encountered among some other 4-amino-quinolines including amodiaquine) becomes aggravated during paroxysmal malarial suppressive chemotherapy with the drug form the basis of this paper. Physiological itching has been linked to the concept of 'spontaneous itch', as compared to pathological itching which has been associated with another concept of 'itching hyperexcitability', and the pathophysiology of pruritus, including the involvement of peripheral and central (neuropeptide) mediators of itch, were considered. The modulating function of spinal and supraspinal 'gateway control' mechanisms, which have been used to explain the overriding effect of pain-over-itch sensation, were also considered and related to itching hyperexcitability. From current data and the records of previously-published reactions to chloroquine, during fever or malarial chemotherapy in man and some mammals, the possible involvement of racial and skin pigment factors, histamine factor, other peripheral mediators of itch, tissue pharmacokinetic factors, central mediators of itch, pyrogenic haemodynamics, and 'gateway' modulation in producing enhanced pruritic reaction during chloroquine antimalarial chemotherapy, were examined in relation to the aggravating role of ischaemia on itch excitability. A trilateral approach to the clinical management of chloroquine-induced pruritus among patients with malaria has been used. In line with the principles of clinical treatment of severe generalized pruritus of uncertain aetiology, this approach has been adapted to reflect the epidemiological, clinical and pathophysiological variables that appear to influence chloroquine-induced pruritus.