From the most basic of nervous systems to the intricate circuits found within the human brain, a fundamental requirement of neuronal function is that it be malleable, altering its output based upon experience. A host of cellular proteins are recruited for this purpose, which themselves are regulated by protein phosphorylation. Over the past several decades, research has demonstrated that the Ca(2+) and calmodulin-dependent protein phosphatase calcineurin (protein phosphatase 2B) is a critical regulator of a diverse array of proteins, leading to both short- and long-term effects on neuronal excitability and function. This review describes many of the influences of calcineurin on a variety of proteins, including ion channels, neurotransmitter receptors, enzymes, and transcription factors. Intriguingly, due to the bi-directional influences of Ca(2+) and calmodulin on calcineurin activity, the strength and duration of particular stimulations may cause apparently antagonistic functions of calcineurin to work in concert.