Microglia and neurons have extensive bidirectional communication in both physiological and pathological brain states, which plays an important role in the establishment of brain homeostasis. It has been found that chemokine CX3CL1 and its receptor CX3CR1 play an important role in intercellular crosstalk between microglia and neurons, so the CX3CL1-CX3CR1 axis may become a new target for various neurodegenerative diseases, mental disorders and other pathological brain states. Here, we review the recent studies on the role of CX3CL1-CX3CR1 signaling axis in microglia's crosstalk with neurons.