Through in silico subtraction and microarray analysis, we identified mouse Gpr149, a novel, oocyte-enriched transcript that encodes a predicted orphan G-protein-coupled receptor (GPR). Phylogenetic analysis of GPR149 from fish to mammals suggests that it is widely conserved in vertebrates. By multitissue RT-PCR analysis, we found that Gpr149 is highly expressed in the ovary and also in the brain and the digestive tract at low levels. Gpr149 levels are low in newborn ovaries but increase throughout folliculogenesis. In the ovary, we found that granulosa cells did not express Gpr149, whereas germinal vesicle and meiosis II stage oocytes showed high levels of Gpr149 expression. After fertilization, Gpr149 expression declined, becoming undetectable by the two-cell stage. To study the function of GPR149 in oocyte growth and maturation, we generated Gpr149 null mice. Surprisingly, Gpr149 null mice are viable and have normal folliculogenesis, but demonstrate increased fertility, enhanced ovulation, increased oocyte Gdf9 mRNA levels, and increased levels of FSH receptor and cyclin D2 mRNA levels in granulosa cells. Thus, Gpr149 null mice are one of the few models with enhanced fertility, and GPR149 could be a target for small molecules to enhance fertility in the assisted reproductive technology clinic.