Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to "rewired" MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.