The rod photoreceptor-specific neural retina leucine zipper protein Nrl is essential for rod differentiation and plays a critical role in regulating gene expression. In the mouse retina, rods account for 97% of the photoreceptors; however, in the absence of Nrl (Nrl-/-), no rods are present and a concomitant increase in cones is observed. A functional all-cone mouse retina represents a unique opportunity to investigate, at the molecular level, differences between the two photoreceptor subtypes. Using mouse GeneChips (Affymetrix), we have generated expression profiles of the wild-type and Nrl-/- retina at three time-points representing distinct stages of photoreceptor differentiation. Comparative data analysis revealed 161 differentially expressed genes; of which, 78 exhibited significantly lower and 83 higher expression in the Nrl-/- retina. Hierarchical clustering was utilized to predict the function of these genes in a temporal context. The differentially expressed genes primarily encode proteins associated with signal transduction, transcriptional regulation, intracellular transport and other processes, which likely correspond to differences between rods and cones and/or retinal remodeling in the absence of rods. A significant number of these genes may serve as candidates for diseases involving rod or cone dysfunction. Chromatin immunoprecipitation assay showed that in addition to the rod phototransduction genes, Nrl might modulate the promoters of many functionally diverse genes in vivo. Our studies provide molecular insights into differences between rod and cone function, yield interesting candidates for retinal diseases and assist in identifying transcriptional regulatory targets of Nrl.