Malaria is responsible for around 3 million deaths annually, the majority of cases being in sub-Saharan Africa. There is a dire need for new and effective drugs to combat the disease. The South African Malaria Initiative is a national network of malaria researchers who are utilising new tools in functional genomics and gene expression to speed up the drug discovery process. Functional genomics has applications in drug discovery to determine the response of an organism to drug challenge and to validate new drug targets. The application of functional genomics in Plasmodia is still in its infancy but early results are promising. The design of drug leads based on identified drug targets requires that the target be produced in sufficient quantities for detailed structural, functional and inhibition studies to be undertaken. This is usually achieved by expression of the protein of interest in a heterologous host, most commonly E. coli. However, proteins from P. falciparum are known to be notoriously difficult to express in heterologous hosts, partly due to their extremely high A-T content. Novel approaches are being developed to increase the number of Plasmodial proteins that can be solubly expressed in heterologous systems.