To study function of widely expressed essential genes, we established a conditional knockout system for cone photoreceptor cells. Our goal is to generate a useful genetic system that can be utilized to disrupt gene function efficiently in cone photoreceptor cells. Functional assay using a Cre-activatable lacZ reporter gene suggested that HRGP-cre mice had widely expressed functional Cre in cone photoreceptors. Since nearly all cone photoreceptor cells express Cre in our transgenic mice, they will be efficient in carrying out Cre-mediated gene activation and inactivation in both M- and S-cone photoreceptors. In addition, we have not observed any apparent ectopic expression in HRGP-cre mice (Le et al., 2004); thus, conditional knockout of essential genes with these mice is not likely to cause any detrimental effect in non-ocular tissues.