During mouse parental behavior, neurons in the dorsal medial preoptic area (MPOAd) are activated and express transcription factors such as c-Fos and FosB. FosB-knockout mice are reported to be defective in parental care. To clarify molecular signaling responsible for parental behavior, we investigated gene expression profiles in the MPOAd of parental versus nonparental mice. We identified upregulation of NGFI-B, SPRY1, and Rad in parental mice, together with c-Fos and FosB. A common inducer of these genes, the extracellular signal regulated kinase (ERK) was phosphorylated in MPOAd neurons upon pup exposure. Pharmacological blockade of ERK phosphorylation inhibited the FosB upregulation in MPOAd, and the initiation of pup retrieving in virgin female mice, but did not affect the established parenting in parous females. Furthermore, induction of SPRY1 and Rad was impaired in MPOAd of nonparental FosB-knockout mice. These results suggest the pivotal role of ERK-FosB signaling in the initiation of parental care.