Protein farnesyl transferase inhibitors (PFTIs) have been developed as oncology therapeutics but recent studies have supported the use of PFTIs for the treatment of eukaryotic pathogens. Data supporting PFTIs for the treatment of African sleeping sickness caused by Trypanosoma brucei sp, and for the therapy of malaria caused by Plasmodium spp is reviewed. Protein prenylation in T. brucei and P. falciparum has been studied using a variety of techniques, including recombinant and native enzyme assays. Studies have demonstrated farnesylation and geranylgeranylation in these parasites. A variety of PFTIs have shown growth inhibition activity and killing of T. brucei and P. falciparum, yet not all mammalian PFTIs are active on parasitic PFTs. Protein farnesyl transferase as well as protein geranylgeranyl transferase type II enzymatic activities have been demonstrated in T brucei and P. falciparum, but protein geranylgeranyl transferase type I activity may be lacking from these parasites, perhaps explaining the extreme sensitivity of these organisms to PFTIs compared with mammalian cells. Given that PFTIs are relatively non-toxic in short-term administration to humans, PFTIs specific to parasites are not required for therapy. Thus, the challenge in PFTI drug development is not to identify selective antiparasite compounds, but to identify compounds with sufficient potency and pharmacokinetic properties to produce satisfactory drugs for malaria and African sleeping sickness.