Dysregulated pH is recognized as a hallmark of cancer. Many cancer-associated cellular processes are altered by changes in pH, including proliferation, apoptosis evasion, metabolic adaptation, cell migration, and tumorigenesis. We describe how both intracellular pH (pHi) and extracellular pH (pHe) are altered in cancer progression due to dysregulation of membrane transport proteins. pH-sensitive proteins, known as pH sensors, then modify their behavior in response to this altered pH microenvironment of cancer, further exacerbating the cancerous phenotype. Obtaining a mechanistic understanding of how this pH change is driven is critical for designing anti-cancer therapeutics. These therapeutics include drugs that are more effective in an altered pH microenvironment, and drugs that combat further pH dysregulation and restore normal pH to the tumor.