Genetic studies on PARK genes have identified dysfunction in proteasomal, lysosomal, and mitochondrial enzymes as pathogenic for Parkinson’s disease(PD). We review the role of these and similar enzymes in mediating innate immunesignaling. In particular, we have identified that a number of PARK gene products as well as other enzymes have roles in innate immunesignaling as well as DNA repair and regulation biquitination, mitochondrial functioning, and synaptic trafficking. PD enzymatic dysfunction is likely to contribute to inadequate innate immune responses to a variety of extra-and intracellular stimuli, with a number of the innate immunity related enzymes found in the characteristic Lewy body pathology of PD. The decrease in innate immunity in PD is associated with an increase in markers of adaptive immunity, and recent GWAS studies have identified variants in human leukocyte antigen region asassociated with late-onset sporadicPD(Hamzaetal.,2010;Hill-Burnsetal.,2011). Intriguing newdata also suggest that peripheral immune responses maybe involved, giving some potential to alleviate such peripheral dysfunction more directly in patients with PD. It is now important to identify the cell type specific immune responses contributing to the initial changes that occur in PD, as well as to the propagating immune responses important for the progression of PD pathology between cells and within the brain. Overall, a complex interplay between different types of immunity appear to be involved in the underlying pathology of PD.