The origin of mutations was a field of heavy discussions between proponents of Darwinism and those of Lamarckism. The major issue was to define an experimental approach that would unambiguously discriminate between mutations occurring at random and mutations caused by the selective agent used to reveal their existence. In the case of bacteria that became resistant to the lytic action of a bacteriophage, the hypotheses were labeled “mutation to immunity” versus “acquired immunity”. Luria and Delbrück realized that the variations observed in the number of resistant bacteria in different parallel cultures were intimately linked to the mutation hypothesis. This exceptional collaboration between a theoretical physicist and a bacteriologist is a perfect example of interdisciplinary work, while these two “enemy aliens” were working in the USA. At that time, it was not even clear that bacteria had genes and most bacteriology work was only descriptive. The use of a quantitative approach allowed the authors to settle the question. The fluctuation test is a very powerful tool to calculate mutation rates. Soon after, Newcombe did a simple but elegant experiment to demonstrate that the increased number of resistant bacteria that are detected upon clonal expansion reflects both the amplification of preexisting mutants and the continuous occurrence of new mutations.