Best known for its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO-1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function. Under pathological conditions, the regulation of some PICK1-interacting partners is altered, pointing to an involvement of PICK1 in neurological disorders. Also, genetic or pharmacological manipulations of PICK1 expression, localization, or function have been shown to influence several physiological or pathological processes in which putative PICK1 partners are involved. This review will summarize recent experimental observations that highlight the involvement of PICK1 in neurological disorders, including schizophrenia, Parkinson's disease, epilepsy, chronic pain, drug abuse, and amyotrophic lateral sclerosis. Synapse 67:532–540, 2013. © 2013 Wiley Periodicals, Inc.