Itch is a major somatic sensation, along with pain, temperature, and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated with mosquito bite, or a chronic condition, like atopic dermatitis (, ). The origins of the stimulus can be localized in the periphery or systemic, and associated with organ failure or cancer. Itch is also a perception originating in the brain. Itch is broadly characterized as either histamine-dependent (histaminergic) or histamine-independent (nonhistaminergic), both of which are relayed by subsets of C fibers and by the second-order neurons expressing gastrin-releasing peptide receptor (GRPR) and spinothalamic track (STT) neurons in the spinal cord of rodents. Historically, itch research has been primarily limited to clinical and psychophysical studies and to histamine-mediated mechanisms. In contrast, little is known about the signaling mechanisms underlying nonhistaminergic itch, despite the fact that the majority of chronic itch are mediated by nonhistaminergic mechanisms. During the past few years, important progress has been made in understanding the molecular signaling of itch, largely due to the introduction of mouse genetics. In this review, we examine some of the molecular mechanisms underlying itch sensation with an emphasis on recent studies in rodents.