Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been genetically and
functionally linked to Parkinson's disease (PD). The kinase activity of LRRK2 is increased by
pathogenic mutations; therefore, modulation of LRRK2 kinase activity by a selective small-
molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's
disease. This chapter presents a historical overview of the development and bioactivity of
several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase
activity in vitro or in vivo. These compounds are important tools for understanding the
cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-
modifying PD therapies.