This chapter summarizes and updates the work on adenosine A2A receptor antagonists for Parkinson’s disease. Adenosine A2A receptor antagonists were, and still are, a promising non-dopaminergic approach for the potential treatment of Parkinson’s disease. There have been numerous publications, patent applications, and press releases that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson’s disease. There have been many research efforts from various pharmaceutical and academic institutions targeting this receptor, and several compounds have advanced into clinical development. The chapter was broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, SAR, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A2A antagonists, but a few approaches to dual A2A/A1 antagonists and A2A/MAO-B will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials.