Malaria causes significant global morbidity and mortality, and while antimalarial treatments are available, resistance has developed to nearly all frontline medicines. New antimalarial compounds therefore need to be discovered but a major challenge to this is the propensity of the parasites to rapidly develop resistance to new antimalarials. We therefore need to prioritise new compounds that are refractory to resistance. Here we report our development of a series of 2-anilino quinazoline compounds that are rapidly acting against the asexual blood stage of Plasmodium falciparum, the parasite responsible for the majority of morbidity and mortality associated with malaria disease. These compounds are also effective against drug resistant parasites and target multiple species and stages of the malaria parasite’s lifecycle. The 2-anilino quinazolines are also highly effective in mouse models of malaria via an oral route. When developing novel compounds, it is also important to consider the biological mechanism of action. This has proven impossible with the 2-anilino quinazolines as they are refractory to the selection of genetic resistance mutations in their target proteins. Therefore, to understand how these compounds are killing malaria parasites, we have had to employ alternative proteomic, metabolomic and biochemical approaches to define their mechanism of action. Thus far we have found that the 2-anilino quinazolines are likely promiscuous and do not have a single protein target responsible for their mechanism of action. We show that they bind several functionally important parasite proteins including PNP, RACK1 and 14-3-3, however none of these appear to be solely responsible for the quinazoline's mechanism of action.