The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na(+)/H(+) exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis.