The serine/threonine kinase c-Jun N-terminal kinase (JNK) 3 is implicated in the pathogenesis of various disorders ranging from neurodegenerative diseases to inflammation, metabolic disease, diabetes, liver diseases, and cancer. Although the number of publications reporting on JNK3 inhibitors has been decreasing in the last few years, this enzyme still constitutes an attractive target. Within the last years, significant progress in the design of JNK3 inhibitors displaying good to excellent selectivity versus other protein kinases has been achieved. However, the development of a JNK-isoform-selective JNK3 inhibitor, which may serve as a tool compound in animal studies to further evaluate the role of JNK3 as a therapeutic target, is highly desirable. This chapter summarizes the progress in the development of reversible and irreversible inhibitors of JNK3.