Leukemia inhibitory factor (LIF) is a multifunctional neuropoietic cytokine involved in neuronal development. Mice with target disruption of the LIF gene are available due to transgenic technology and biotechnology. However, LIF-deficient mice have been reported to be embarrassingly poor in replacement and display awkward colony phenotypes. From total 265 breeds, significantly smaller breeding rate and litter numbers were observed from homozygous male pairs. And LIF-deficient mouse colony did not follow rules of genetics. Both heterozygote male and homozygote male colonies showed significantly higher male birth rate than the hypothetical value. Taken together, epochal improvement in acquiring transgenic animals may be necessary to facilitate large-scale or long-term studies using the LIF-deficient mice. Therefore, better strategies to assure enough numbers of LIF-deficient mice are imminent. In order to achieve this goal, longterm monitoring of the colony has been performed and possible solutions also have been suggested.