The posttranslational modification of protein prenylation is a covalent lipid modification on the C-terminus of substrate proteins that serves to enhance membrane affinity. Oncogenic proteins such as Ras have this modification and significant effort has been placed into developing inhibitors of the prenyltransferase enzymes for clinical therapy. In addition to cancer therapy, prenyltransferase inhibitors have begun to find important therapeutic uses in other diseases, including progeria, hepatitis C and D, parasitic infections, and other maladies. This review will trace the evolution of prenyltransferase inhibitors from their initial use as cancer therapeutics to their expanded applications for other diseases.