Severe psychological or mental pain, on one hand, is defined as an experience of unbearable torment which can be associated with a psychiatric illness (e.g., Posttraumatic Stress Disorder) or a tragic loss such as the death of an important person. On the other hand, the dominant model in physical pain perception describes a “neuromatrix” which is activated in response to painful stimuli and is also regulated by psychological factors. It was reported that emotions interact with the somato-sensory-discriminant system and that this interaction can produce a sensitization or desensitization to painful stimuli. Further, hypnotically suggested pain seems to produce a pattern of brain region activation similar to that associated with an actual painful stimulus, indicating that mechanisms in the central nervous system may be sufficient to produce the experience of pain even in the absence of external stimulation of the peripheral nerves. It was also proposed by the interpersonal-psychological theory of suicide that exposure to painful and provocative experiences such as combat contribute to fearlessness concerning death and increased physical pain tolerance, which serve to enhance the individual's capability to adopt suicidal behavior. It was further reported that psychological pain is a useful and unique construct in patients with major depressive episodes that can be reliably assessed and may aid in the evaluation of suicidal risk. However, not only environmental factors but also genetic predisposition seem to play an important role in the pathogenesis of suicidal behavior. The interplay between genes and environmental factors involved in suicidal behavior will be discussed.