Pain, albeit unpleasant, is necessary to prevent a worsening of lesion when tissue damage occurs. Nonetheless, certain pathological conditions are characterized by an aberrant activation of nociceptive pathways. The synapse between primary afferent fibres and neurons in the spinal dorsal horn represents the first site of integration of pain signals in the nervous system and is therefore considered a strategic area for pharmacological control of pathological pain. Many efforts have been made in the last decades to understand which neurotransmitters and/or receptors are involved in the neuron-to-- neuron communication at this level and how their contribution is altered under pathological pain. Unfortunately, in spite of the large amount of information provided by fundamental research in the pain field, certain forms of pathological pain are still untreatable and the repeated use of powerful analgesics, such as morphine, is strongly limited by the development of tolerance and withdrawal syndromes. In the attempt to find new cellular mechanisms underlying altered pain transmission, recent studies have brought the attention beyond neuronal networking, by focusing on the role played by non-neuronal cells. In this respect, increasing amounts of evidence indicate microglia as an active player translating specific extracellular signals into significant alterations of neuronal excitability. Indeed, microglia has been shown to respond to a broad range of pain-associated molecules, including nucleotides, neuropeptides and opioids. Activated microglia in turn releases inflammatory cytokines, nitric oxide, BDNF and other mediators that may dramatically influence the activity of dorsal horn neurons. In this chapter, we will review the most significant findings concerning the communication between spinal microglia and dorsal horn neurons and discuss the potential translation of these findings in pain therapy.