The transmissible spongiform encephalopathies are rapidly progressive and invariably fatal neurodegenerative diseases for which there are no proven efficacious treatments. Many approaches have been undertaken to find ways to prevent, halt, or reverse these prion diseases, with limited success to date. However, as both our understanding of pathogenesis and our ability to detect early disease increases, so do our potential therapeutic targets and our chances of finding effective drugs. There is increasing pressure to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) has been shown to be transmissible by blood, and to find non-toxic preventative therapies, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD). Within the realm of chemotherapeutic approaches, much research has focussed on blocking the conversion of the normal form of prion protein (PrPc) to its abnormal counterpart (PrPres). Structurally, these chemotherapeutic agents are often polyanionic or polycyclic and may directly bind PrPc or PrPres, or act by redistributing, sequestering, or downregulating PrPc, thus preventing its conversion. There are also some polycationic compounds which proport to enhance the clearance of PrPres. Other targets include accessory molecules such as the laminin receptor precursor which influences conversion, or cell signalling molecules which may be required for pathogenesis. Of recent interest are the possible neuroprotective effects of some drugs. Importantly, there is evidence that combining compounds may provide synergistic responses. This review provides an update on current testing methods, therapeutic targets, and promising candidates for chemical-based therapy.