AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor trafficking is a fundamental mechanism for regulating synaptic strength, and hence may underlie cellular processes involved in learning and memory. PICK1 (protein interacting with C-kinase) is a PDZ and BAR domain-containing protein that has recently emerged as a key regulator of AMPA receptor traffic. Via the PDZ domain, PICK1 interacts directly with AMPA receptor subunits and is involved in the regulated removal of AMPA receptors from the synaptic plasma membrane. PICK1 has the ability to functionally interact with a number of cellular processes, including calcium signaling, actin polymerisation and phospholipid membrane architecture. In this review, I summarize recent findings that describe the importance of PICK1 in neurons and its specific molecular characteristics that enable it to regulate AMPA receptor trafficking.