CREB (Cyclic-AMP Response Element Binding) proteins are transcription factors which bind to certain sequences called CRE elements in DNA and thereby increase or decrease the transcription of certain genes. CREB proteins are active in many animals, including humans. The typical (somewhat simplified) sequence of events is as follows: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cyclic-AMP or Ca²⁺, which in turn activates a protein kinase. This protein kinase moves to the cell nucleus, where it activates a CREB protein. The activated CREB molecule then binds to a CRE element and thereby switches certain genes on or off.

CREB proteins in neurons are involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, and in rats. They are necessary for the late stage of long term potentiation. There are activator and repressor forms of CREB. Fruit flies genetically engineered to overexpress the activator form have been shown to learn significantly faster than wild-type flies: they readily form long-term memories after only a single training, while wild-type flies require several spaced repetitions.

In humans, abnormalities of the CREB protein gene CBP is associated with Rubenstein-Taybi syndrome.