Cognitive and affective strategies are frequently used in clinical practice to modulate pain perception. They seem to rely on a descending neural system, which is able to inhibit the afferent nociceptive signal. Herein, we will review experiments on healthy volunteers, which explored the central mechanisms involved in the change in pain perception due to the modulation of attention, expectations or mood. A growing understanding of the cognitive and emotional modulation of pain perception has validated empirical practices in the acute pain context. This body of work, associated to the investigation of the dysfunction of this modualtion in chronic pain patients, could lead to developing new therapies, which would complement current treatments.