Progress in understanding the role of alpha-synuclein (aSyn) as a driver of synucleopathies such as Parkinson’s disease (PD) led to the development of a novel class of drug candidates characterized by the potential for disease modification. The first member of this new class, the AFFITOPE Parkinson vaccine candidate PD01A [1] – developed by the Austrian biotechnology company AFFiRiS – has now entered the phase of clinical development (NCT01568099). PD01A is a peptide-carrier conjugate vaccine. Antibodies elicited by PD01A react with aSyn and spare beta-synuclein, a family member not involved in pathology but able to compensate physiological aSyn functions. PD01A demonstrated proof-of-concept in a series of transgenic synucleopathy models. These data, along with favorable preclinical toxicity studies, led AFFiRiS to initiate a Phase I study in early PD patients. The AFFiRiS program is the first ever to treat PD patients with an aSyn-lowering vaccine. Further aSyn-addressing candidates, including monoclonal antibodies and small molecules inhibiting aSyn aggregation, are being developed by other companies; some of them are expected to join PD01A soon in the clinical arena. The challenges that this new drug class faces fundamentally differ from those the currently approved symptomatic drugs had to master. Demonstration of a disease-modifying activity will presumably require identification of patients in early stages of their disease with a high specificity, as well as the availability of biomarkers and clinical end points informing on a change, such as slowing/halting, of the disease process.