Chemicals play a crucial role in neurophysiological and neuropathological processes. By regulating the concentration of specific chemicals, receptors on the neuron cell membrane can be modulated to activate or inhibit, thereby influencing specific ion channels and facilitating neuromodulation. This review introduces several chemical modulation techniques, such as microinjection, electrode/nanoparticle-based chemical delivery methods, in situ electrochemical synthesis and chemogenetics. While these techniques show promise in expanding the application of chemical neuromodulation, they currently exhibit different degrees of shortcomings and room for improvement. This review summarizes the opportunities and challenges for chemical neuromodulation methods and provide an outlook for their prospects in the future.