The sodium hydrogen exchanger isoform one is a critical regulator of intracellular pH, serves as an anchor for the formation of cytoplasmic signaling complexes, and modulates cytoskeletal organization. There is a growing interest in the potential for sodium hydrogen exchanger isoform one as a therapeutic target against cancer. Sodium hydrogen exchanger isoform one transport drives formation of membrane protrusions essential for cell migration and contributes to the establishment of a tumor microenvironment that leads to the rearrangement of the extracellular matrix further supporting tumor progression. Here, we focus on the potential impact that an inexpensive, $100 genome would have in identifying prospective therapeutic targets to treat tumors based upon changes in gene expression and variation of sodium hydrogen exchanger isoform one regulators. In particular, we will focus on the ezrin, radixin, moesin family proteins, calcineurin B homologous proteins, Ras/Raf/MEK/ERK signaling, and phosphoinositide signaling as they relate to the regulation of sodium hydrogen exchanger isoform one in cancer progression.