Objective: A common feature of tumours is a shift in cellular metabolism generating a high acid load in the tumour microenvironment. In addition, hypoxia contributes to the exacerbation of tumour extracellular acidosis. The potential toxic effects of low extracellular pH (pHe) are counteracted by cellular mechanisms including potassium channels and the H+/K+ ATPase proton pump. We hypothesize that regulation of pH of the tumour microenvironment affects cancer cell proliferation through pH sensitive membrane proteins. The present study was aimed at investigating the effect of pH and cellular pH regulating mechanisms on proliferation of the SKOV3 and MG63 cell lines. Materials and method: Ovarian cancer (SKOV3) and osteosarcoma (MG63) cell lines were cultured media of Extracellular pH (pHe) ranging from 6 to 7.5 . Cells were also maintained at 3% O2 to induce a low pHe and to compare their response to alterations in pHe in normoxia. Cell proliferation and cell viability assays were performed in the presence and absence of drugs known to inhibit the H+/K+ATPase proton pump (omeprazole), EAG channel (E-4031) and the pH-sensitive potassium channel, TASK3 (methanandamide) over 24 and 72 hour time-points using MTS cell proliferation assay. Data was compared using one-way ANOVA. All experiments were repeated thrice. Result: The SKOV3 and MG63 cells showed an increased rate of proliferation after culturing for 72 hours in pH 6.0 compared with pH 7.5 (p<0.05). E-4031 and methanandamide at 0.1 μM increased cell death by 35% and 20% respectively in SKOV3 and MG63 cells after 72 hours in pHe 6.0 in comparison to pHe 7.5 (p<0.05). Omeprazole at 10 μg/ml significantly decreased cell proliferation of MG63 cells within 24 hours at a pHe of 6.5 in comparison to cells treated with omeprazole at pHe 7.5 (p<0.05). Discussion and Conclusion: Inhibitors of potassium channels and proton pumps elicited a variable response from proliferation experiments with MG63 and SKOV3 cell lines. A change in pHe influenced proliferation, indicating dependence on cellular pH regulating systems and membrane protein. The presence of these pH regulating systems often works in correlation with change in cellular metabolism owing to altered intracellular pH and pHe. Further investigation is required to understand the fundamentals of pH regulatory systems to meet the challenge of targeting tumour metabolism and acidosis as an anti-cancer therapy.