Microenvironment acidity is a well-established chemical signature of solid tumours. It arises from upregulated cancer metabolism which loads the extracellular space with large quantities of CO2 and lactic acid, in combination with aberrant blood perfusion which fails to adequately wash away these acids (1). It is now recognised that tumour acidosis is not merely an accumulation of end-products, but a source of feedback that can influence disease progression by selecting phenotypes compatible with the ambient pH (2). Whilst this somatic evolution process has a precedent in, for instance, hypoxia-driven carcinogenesis, the mechanisms of acid-selection remain unclear. The ability to survive and thrive at any given milieu pH is determined by the ensemble pH-sensitivity of proteins, most of which have multiple protonatable sites. I will talk about our ongoing efforts to characterise acid-sensing and acid-handling in colorectal cancer (CRC). To gain new insights, we are screening a large panel of over 100 CRC lines for phenotypes related to pH. These lines have been sequenced for genotype (e.g. mutations) and gene expression at mRNA level (by microarray), thus allowing us to correlate genetics with function. The size of this panel of cell lines provides adequate statistical testing power and encompasses most permutations of the common mutations found in human colorectal tumours (3). The readouts we use to interrogate “pH phenotype” include cell survival, lumen formation and steady-state intracellular pH measured using a high-throughput plate imaging system over a range of medium pH. Using these criteria, we can categorise CRC cell lines as acid-sensitive or acid-resistant. Most cancer cells are believed to be devoid of cell-to-cell diffusive coupling through connexin-assembled gap junctions. Thus, it is commonly assumed that cancer cells function independently of one another, and do not exchange signals and metabolites across a cytoplasmic syncytium. By imaging the diffusive spread of fluorescent dyes, we can test for diffusive coupling in monolayers. We find that some CRC lines or even their distinct subpopulations manifest strong diffusive coupling. Such heterogeneity may influence the physiological behaviour of cancer cells in tumours, which inherently feature standing gradients that can drive fluxes through such a syncytium (4). The pH landscape of the tumour milieu is not solely shaped by cancer cells and vasculature but also by numerous stromal components that can engage in acid-base transport. Myofibroblasts are the major stromal component in the colon, and our findings show that these assemble into a syncytium with a powerful capacity to absorb acids secreted by cancer cells. Furthermore, this stromal function can be enhanced by cytokines secreted by CRC cells, thus providing a means by which cancer cells can subordinate myofibroblasts (5). In summary, there are multiple players involved in establishing the acidic tumour microenvironment, and complex mechanisms through which cancer cells respond to this chemical selection pressure.