Cellular protein kinases are involved in diverse normal cellular functions. Many types of dysregulation of protein kinases are the molecular basis for development of common cancers and neurodegenerative diseases. More than 80 small-molecule protein kinase inhibitors are available now and approved by the US Food and Drug Administration for successful treatment of cancers and neurodegenerative diseases. Newly designed protein kinase inhibitors and related forms of therapy based on a greater understanding of molecular mechanisms have diminished the appearance of disease resistance to protein kinase inhibitors and other side effects. These advances will further promote the success of protein kinase inhibitors in treatment of common cancers, Alzheimer's disease, and other neurodegenerative conditions.