JNK is involved in a broad range of physiological processes. Several inflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s and Parkinson’s disease have been linked with the dysregulated JNK pathway. Research on disease models using the relevant knockout mice has highlighted the importance of specific JNK isoformsin-particular disorders and has stimulated further efforts in the drug-discovery area. However, most of the experimental evidence for the efficacy of JNK inhibition in animal models is from studies using JNK inhibitors, which are not isoform selective. Some of the more recent compounds exhibit good oral bioavailability, CNS penetration and selectivity against the rest of the kinome. Efforts to design isoform-selective inhibitors have produced a number of examples with various selectivity profiles. This article presents recent progress in this area and comment on the role of isoform selectivity for efficacy.