The brain plays a prominent role in the generation and modulation of pain. It contains powerful endogenous pain modulatory systems that can be engaged in a beneficial way by therapeutical intervention. In contrast, pain chronification is associated with maladaptive structural and functional changes that may shift the balance of the modulatory systems. Although pain from myofascial trigger points (MTrPs) is highly prevalent, little is known about its brain manifestations and modulation. Recent neuroimaging data suggest that hyperalgesia from MTrPs is processed in similar regions as hyperalgesia from other pain conditions. However, abnormal hippocampal hypoactivity suggests that dysfunctional stress responses may play an important role in the generation and maintenance of hyperalgesia from MTrPs. Other data suggest that short-term pain relief obtained with intramuscular electrostimulation within an MTrP is partially due to descending pain inhibitory mechanisms.