The estimated worldwide incidence of Plasmodium falciparum malaria is about 500 million cases a year. In tropical areas, the dramatic increase of resistance to most antimalarial drugs is directly responsible for persistent widespread high endemicity and related morbidity. The search to identify new drug targets and agents is a high priority. However the value of standard pharmacological research methods is greatly diminished by technical problems involving in vitro and in vivo modeling of malaria infection. In recent decades new mathematical tools have been developed to predict drug properties and to estimate biological activity in silico. Various approaches have been proposed based on 2D or 3D descriptions of the chemical structure of the drug and target followed by mathematical and statistical characterization of their interaction. These techniques are now widely used in medicinal chemistry and have proven their efficacy for screening the anti-malarial activity of numerous molecules in large databases and for virtual synthesis. Incorporating new knowledge from the genomic studies of Plasmodium has markedly increased the performance and range of application of these tools for identifying new drug targets against malaria.