With the advent of large scale genomics or gene expression efforts, hundreds of genes have been identified with potential roles in normal development and disease pathogenesis such as inflammation. One key question is to validate essential genes involved in fundamental physiology and disease from genes and pathways that serve bystander functions. We have developed the first haploid embryonic stem cells and technologies for genome-wide mutagenesis that can be used for rapid forward genetics experiments. In essence we can now saturate mutagenesis of the entire genome in a single day. We can also use the power of stem cell biology for reverse genetics experiments and have already developed more than 70000 haploid ES cell clones that carry defined integrations of bar-coded and repairable vectors. I will present examples for both forward and reverse genetics screens. Thus, we can combine the power of a haploid mammalian genome with the differentiation potential of embryonic stem cells.