Indirubin is the active ingredient in many Chinese materia medica and mainly used to treat leukemia. It has been founded as leading inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) by competing with ATP binding sites. Increasing new findings pointed out that the unique chemical structure of indirubin could contribute to the polypharmacological activities particularly against cancer and neurodegeneration therapy while these diseases shared common molecular link on abnormal phosphorylation of CDKs and GSK-3. In this review, the underlying mechanisms of dual actions of indirubin and its structurally similar compounds on therapy of cancer and neurodegenerative diseases are presented.