Guanylyl cyclase (GC) converts GTP into cGMP, an intracellular second messenger involved in a wide variety of cellular, developmental, and neuronal processes. Medaka fish, a small teleost, Oryzias latipes has been used to study organization and transcriptional regulation of the guanylyl cyclase gene family. Medaka fish expresses virtually all types of GCs found in mammals. Eight membrane GCs (OlGC1-7 and OlGC-R2) have been identified in medaka fish. OlGC1, OlGC2, and OlGC7 belong to the natriuretic peptide receptor subfamily. OlGC6 is a homologue of the mammalian GC-C, an enterotoxin/guanylin receptor, expressed predominantly in the intestine. OlGC3, OlGC4, OlGC5, and OlGC-R2 are members of the sensory organ-specific GC subfamily where they are differentially expressed in rods and cones of the retina and in the pineal organ. Complete genomic DNA sequences have been determined for the OlGC1 and OlGC6 genes. Their exon-intron organization is highly conserved between fish and mammals. The medaka fish genome also contains genes encoding α and β subunits of the cytoplasmic form of GC (soluble GC), which is activated by nitric oxide. The two subunit genes are closely linked in tandem in the order of α and β. Function of cis-regulatory regions of medaka fish GC genes have been investigated in transgenic medaka fish embryos and in mammalian cell lines. The upstream region of the α subunit gene of soluble GC appears to regulate expression of both α and β subunit genes, suggesting a mechanism of coordinated transcription of the two subunit genes. The upstream regions sufficient for the tissue-specific expression of sensory organ GCs also have been determined by transgenic analysis. Readiness for genetics and genetic manipulations in medaka fish would make this small fish a useful experimental system for studying the regulation of gene expression and roles of the guanylyl cyclase family in vertebrates.