Itch is one of the most distressing sensations that substantially impair quality of life. It is a cardinal symptom of many skin diseases and is also caused by a variety of systemic disorders. Unfortunately, currently available itch medications are ineffective in many chronic itch conditions, and they often cause undesirable side effects. To develop novel therapeutic strategies, it is essential to identify primary afferent neurons that selectively respond to itch mediators as well as the central nervous system components that process the sensation of itch and initiate behavioral responses. This review summarizes recent progress in the study of itch, focusing on itch-selective receptors, signaling molecules, neuronal pathways from the primary sensory neurons to the brain, and potential decoding mechanisms by which itch is distinguished from pain.