Neurotensin (NT) can produce a profound analgesia or enhance pain responses, depending on the circumstances. Recent evidence suggests that this may be due to a dose-dependent recruitment of distinct populations of pain modulatory neurons. NT knockout mice display defects in both basal nociceptive responses and stress-induced analgesia. Stress-induced antinociception is absent in these mice and instead stress induces a hyperalgesic response, suggesting that NT plays a key role in the stress-induced suppression of pain. Cold water swim stress results in increased NT mRNA expression in hypothalamic regions known to project to periaqueductal gray, a key region involved in pain modulation. Thus, stress-induced increases in NT signaling in pain modulatory regions may be responsible for the transition from pain facilitation to analgesia. This review focuses on recent advances that have provided insights into the role of NT in pain modulation.