- Fibromyalgia affects more than 5 million people in the United States and has a detrimental impact on individuals' quality of life. Current pharmacological treatments provide limited benefits to relieve the pain of fibromyalgia, along with a risk of adverse effects; a scenario that explains the increasing interest for multimodal approaches. A tailored strategy to focus on this dysfunctional endogenous pain inhibitory system is transcranial direct current stimulation (tDCS) of the primary motor cortex. By combining tDCS with aerobic exercise, the effects can be optimized. Areas covered: The relevant literature was reviewed and discussed the methodological issues for designing a mechanistic clinical trial to test this combined intervention. Also, we reviewed the neural control of different pathways that integrate the endogenous pain inhibitory system, as well as the effects of tDCS and aerobic exercise both alone and combined. In addition, potential neurophysiological assessments are addressed: conditioned pain modulation, temporal slow pain summation, transcranial magnetic stimulation, and electroencephalography in the context of fibromyalgia. Expert commentary: By understanding the neural mechanisms underlying pain processing and potential optimized interventions in fibromyalgia with higher accuracy, the field has an evident potential of advancement in the direction of new neuromarkers and tailored therapies.