There is a fundamental gap in our understanding of how horizontal gene transfer contributes to the enormous range of genetic variations that are observed among bacteria. The objective of our study was to better understand how the acquisition of genetic material by natural transformation is regulated within a population of Vibrio cholerae cells. V. cholerae is an aquatic bacterium and a facultative human pathogen. It acquires natural competence for transformation in response to changing environmental signals, such as the presence of chitinous surfaces, the absence of monomeric sugars and quorum sensing-linked autoinducers. The latter play a distinctive role in V. cholerae as they fine-tune a switch from the degradation of extracellular DNA toward the uptake of intact DNA strands in competence-induced cells. The link between quorum sensing and natural competence for transformation will be discussed. Furthermore, we speculate on the overrepresentation of transformation-negative strains of V. cholerae in patient-derived culture collections, which might be the result of a biased sampling strategy as virulence and natural transformation are contrarily regulated by the quorum sensing network.