This article is focused on problems related to application of mice knock-outs used in neurobiology. Diverse genetical background, genotype of mouse strain 129 (the main source of embryonic stem cells), developmental defects, pleiotropy and compensation make the interpretation of results from knock-out models difficult. The use of time- and space-specific "knock-outs of second generation", introduction of transgenes that reverse the effect of gene knock-outs, blocking of genes by antisense mRNA or point mutations may aid in eliminating some of these problems.