Gene targeting by homologous recombination is a powerful technique, generating mouse strains with defined mutations in their genome. These genetically modified, 'designer' animals allow us for the first time to ask simple questions about elaborate and complex biological systems. Dissecting the function of individual components of the immune system is a perfect application of this technology. Although the techniques involved in the generation of gene knock-out mice are increasingly well defined, to many immunologists the language and concepts are confusing. This review presents the essentials of the technology in a form digestible by the non-expert.