Malaria is a major health and economic threat to about 40% of the world's population. The absence of effective vaccines and widespread resistance to many of the current antimalarials make this disease an urgent target for the scientific community. As a developing world disease, most of the efforts towards new drugs have been from academic and government supported projects. This has recently changed with the emergence of new funding mechanisms and public-private partnerships (PPP). The purpose of this review is to highlight the different approaches used to discover new antimalarial agents, including target-based approaches, derivatization of known antimalarial pharmacophores, drug repositioning from non-malaria indication and cell-based screening. Specific examples are provided to illustrate the pros and cons in the context of how to best address the ever-increasing drug resistance and how to cost-effectively identify new antimalarials. More attention is given to relatively mature programs that have gone through extensive SAR study, pharmacology and/or toxicity studies in the last ten years.