Neuromodulation, including invasive and non-invasive stimulation, has been used to treat intractable chronic pain. However, the mechanisms by which neuromodulation produces antinociceptive effect still remain uncertain. Optogenetic manipulation, a recently developed novel approach, has already proven its value to clinicians by providing new insights into mechanisms of current clinical neuromodulation methods as well as pathophysiology of nervous system diseases at the circuit level. Here, we discuss the principles of two neuromodulation methods (deep brain stimulation and motor cortex stimulation) and their applications in pain treatment. More important, we summarize the new information from recent studies regarding optogenetic manipulation in neuroscience research and its potential utility in pain study.