In this chapter we discuss the many recent discoveries of the mechanisms by which itch is transmitted: the neurotransmitters and the responses they trigger, the mechanisms by which specific neuronal targets are activated, and the specificity of the pathways. Current data reveal that DRG neurons and spinal cord cells use a remarkably selective set of transmitters to convey pruritic information from the periphery to the brain: glutamate and Nppb are released from primary itch-sensory cells; these molecules activate secondary spinal cord pruriceptive-specific neurons, which in turn utilize Grp to activate tertiary pruriceptive-selective neurons. Intersecting this basic linear excitatory pathway, inhibitory input from dynorphin and neurons that express the somatostatin receptor modify itch sensation. Cumulatively, these studies paint an elegantly simple picture of how itch signals are transformed and integrated in the spinal cord and open new avenues for research efforts aimed at understanding and better treating itch.