The glutamate/cystine antiporter system x(c)(-) transports cystine into cells in exchange for glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, and a heavy chain, 4F2, linked by a disulfide bridge. Intracellularly, cystine is reduced into cysteine, the rate-limiting precursor of glutathione (GSH), an important small molecule antioxidant. Several lines of evidence suggest that the expression of xCT and thereby the presence system x(c)(-) activity plays an important role in the brain. First, it regulates extracellular glutamate concentrations. Second, as brain is prone to oxidative stress due to its high oxygen consumption and lipid content, system x(c)(-) by favoring GSH synthesis, may prevent oxidative damage. Thus, to understand how xCT expression and system x(c)(-) activity are regulated in the central nervous system is of utmost importance. In this review, we will summarize the current knowledge about the molecular basis by which xCT expression and system x(c)(-) activity are regulated in neuronal cell lines, especially the hippocampal cell line, HT22. In addition, we will relate these pathways to findings in other cell types, especially those found in the central nervous system. We will focus on the signaling pathways that modulate the transcription of the xCT gene. Furthermore, we describe possible pathways that modify system x(c)(-) activity beyond the level of xCT transcription, including regulation on the level of membrane trafficking and substrate availability, especially the regulation by glutamate transport through excitatory amino acid transporters.