Cooperation between cells in multicellular organisms is essential to ensure the fitness of the whole organism; however, 'cheater' mutants (which do not cooperate but benefit from the cooperation between others) can emerge, lowering fitness unless the organism can re-equilibrate towards cooperation. Here, the authors hypothesized that regulatory mechanisms operate during mammalian development to remove aberrant clones that reduce fitness. To test this, they developed a genome-wide 'cheater screen' in mouse pluripotent stem cells to identify cooperation genes, loss of which would allow cheater mutants to obtain a competitive advantage. Among the genes identified were those encoding p53, topoisomerase 1 and olfactory receptors, knockdown of which allowed mutant cells to expand disproportionately compared with wild-type cells in vitro and in vivo. Thus, these genes seem to have key roles in fostering cell cooperation in mammals.