Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzymes active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.