Tumours have a high metabolic rate, leading to acidosis and hypoxia in poorly perfused regions. Tumour cells have evolved to function in more acidic environments than normal cells. Key pH regulators in tumour cells include carbonic anhydrase isoforms (CA2, CA9, CA12), anion exchangers, Na+/HCO3- co-transporters, Na+/H+ exchangers, monocarboxylate transporters, and the vacuolar ATPase (V-ATPase). These regulators are targeted by small molecules and antibodies in clinical development. Classical cancer drugs do not exploit these mechanisms, making them a new anticancer strategy. The Warburg effect refers to cancer cells' preference for glycolysis and lactic acid fermentation over oxidative phosphorylation, leading to high glucose consumption and lactate production. This creates an acidic tumour microenvironment, which supports tumour growth and metastasis. Tumour cells maintain an alkaline intracellular pH (pHi) and acidic extracellular pH (pHe) through various mechanisms, including ion transporters, proton pumps, and carbonic anhydrases. These pH differences are crucial for tumour cell survival and proliferation. Carbonic anhydrases, particularly CA9 and CA12, are overexpressed in many tumours and play a key role in tumour acidification. Sulphonamides and coumarins are effective inhibitors of these enzymes. Monoclonal antibodies targeting CA9 and CA12 also show promise in cancer therapy. Inhibiting these enzymes can reverse tumour acidification, leading to reduced tumour growth and metastasis. Other pH-regulating proteins, such as anion exchangers, Na+/H+ exchangers, and monocarboxylate transporters, are also targeted. Inhibitors of these proteins can disrupt tumour pH homeostasis, leading to cell death. Proton pump inhibitors (PPIs) and V-ATPase inhibitors may also be effective in targeting tumour acidification. Several compounds, including sulphonamides, coumarins, and monoclonal antibodies, are in clinical development for targeting tumour pH regulation. These agents show promise in reversing tumour acidification and inhibiting cancer cell growth. Combination therapies with these agents and other anticancer drugs may enhance therapeutic outcomes. Overall, targeting pH regulation in tumours represents a promising new approach in cancer therapy.Tumours have a high metabolic rate, leading to acidosis and hypoxia in poorly perfused regions. Tumour cells have evolved to function in more acidic environments than normal cells. Key pH regulators in tumour cells include carbonic anhydrase isoforms (CA2, CA9, CA12), anion exchangers, Na+/HCO3- co-transporters, Na+/H+ exchangers, monocarboxylate transporters, and the vacuolar ATPase (V-ATPase). These regulators are targeted by small molecules and antibodies in clinical development. Classical cancer drugs do not exploit these mechanisms, making them a new anticancer strategy. The Warburg effect refers to cancer cells' preference for glycolysis and lactic acid fermentation over oxidative phosphorylation, leading to high glucose consumption and lactate production. This creates an acidic tumour microenvironment, which supports tumour growth and metastasis. Tumour cells maintain an alkaline intracellular pH (pHi) and acidic extracellular pH (pHe) through various mechanisms, including ion transporters, proton pumps, and carbonic anhydrases. These pH differences are crucial for tumour cell survival and proliferation. Carbonic anhydrases, particularly CA9 and CA12, are overexpressed in many tumours and play a key role in tumour acidification. Sulphonamides and coumarins are effective inhibitors of these enzymes. Monoclonal antibodies targeting CA9 and CA12 also show promise in cancer therapy. Inhibiting these enzymes can reverse tumour acidification, leading to reduced tumour growth and metastasis. Other pH-regulating proteins, such as anion exchangers, Na+/H+ exchangers, and monocarboxylate transporters, are also targeted. Inhibitors of these proteins can disrupt tumour pH homeostasis, leading to cell death. Proton pump inhibitors (PPIs) and V-ATPase inhibitors may also be effective in targeting tumour acidification. Several compounds, including sulphonamides, coumarins, and monoclonal antibodies, are in clinical development for targeting tumour pH regulation. These agents show promise in reversing tumour acidification and inhibiting cancer cell growth. Combination therapies with these agents and other anticancer drugs may enhance therapeutic outcomes. Overall, targeting pH regulation in tumours represents a promising new approach in cancer therapy.