Star­ting two deca­des ago with the dis­co­ve­ries of gene­tic links bet­ween alpha-synu­c­lein and Parkinson’s disea­se risk and the iden­ti­fi­ca­ti­on of aggre­ga­ted alpha-synu­c­lein as the main pro­te­in con­sti­tu­ent of Lewy patho­lo­gy, alpha-synu­c­lein has emer­ged as the major the­ra­peu­tic tar­get in Parkinson’s disea­se and rela­ted synu­clei­nopa­thies. Fol­lo­wing the sug­ges­ti­on that alpha-synu­c­lein patho­lo­gy gra­dual­ly spreads through the ner­vous sys­tem fol­lo­wing a ste­reo­ty­pic pat­tern and the dis­co­very that aggre­ga­ted forms of alpha-synu­c­lein can pro­pa­ga­te patho­lo­gy from one cell to ano­t­her, and ther­e­by pro­bab­ly aggra­va­te exis­ting defi­cits as well as gene­ra­te addi­tio­nal sym­ptoms, the idea that alpha-synu­c­lein is a via­ble the­ra­peu­tic tar­get gai­ned fur­ther sup­port. In this review we descri­be cur­rent chal­len­ges and pos­si­bi­li­ties with alpha-synu­c­lein as a the­ra­peu­tic tar­get. We brief­ly high­light gaps in the know­ledge of the role of alpha-synu­c­lein in disea­se, and pro­po­se that a deeper under­stan­ding of the patho­bio­lo­gy of alpha-synu­c­lein can lead to impro­ved the­ra­peu­tic stra­te­gies. We descri­be several tre­at­ment approa­ches that are cur­r­ent­ly being tested in advan­ced ani­mal expe­ri­ments or alrea­dy are in cli­ni­cal tri­als. We have divi­ded them into approa­ches that redu­ce alpha-synu­c­lein pro­duc­tion; inhi­bit alpha-synu­c­lein aggre­ga­ti­on insi­de cells; pro­mo­te its degra­da­ti­on eit­her insi­de or out­si­de cells; and redu­ce its upt­ake by neigh­bou­ring cells fol­lo­wing release from alrea­dy affec­ted neu­rons. Final­ly, we brief­ly dis­cuss chal­len­ges rela­ted to the cli­ni­cal tes­ting of alpha-synu­c­lein the­ra­pies, for examp­le dif­fi­cul­ties in moni­to­ring tar­get enga­ge­ment and the need for rela­tively lar­ge tri­als of long dura­ti­on. We con­clu­de that alpha-synu­c­lein remains one of the most com­pel­ling the­ra­peu­tic tar­gets for Parkinson’s disea­se, and rela­ted synu­clei­nopa­thies, and that the mul­ti­tu­de of approa­ches being tested pro­vi­des hope for the future.