Current treatments for Parkinson's disease fail to modify disease progression, and the underlying pathogenic mechanisms remain elusive. The identification of specific targets responsible for disease will aid in the development of relevant model systems and the discovery of neuroprotective and neurorestorative therapies. Two promising protein candidates, alpha-synuclein and LRRK2, offer unique insight into the molecular basis of disease and the potential to intervene in pathogenesis. Although multiple lines of evidence support alpha-synuclein and LRRK2 as robust targets for therapy, the connection between protein function and neurodegeneration is unclear. Technology capable of mitigating alpha-synuclein and LRRK2 disease-associated function will ultimately be required before the true value of these proteins as therapeutic targets can be discerned.