Pain is a potent motivator. A nociceptor detects tissue damage. The term ‘pain receptors’ is misleading. There can be pain without tissue damage and tissue damage without pain. Nociceptive and anti-nociceptive pathways are described in the context of the gate theory of pain. The properties of the motivational system of pain are described; for example, flexible strategies for avoiding or minimizing tissue damage and competition with other motivated activities. The brain’s pain matrix is described including (e.g. part of the anterior cingulate cortex). Rats learn to take the side of a T-maze associated with relief of pain, a conditioned place preference. The role of dopamine and opioids is described. A number of contextual factors are described (e.g. control and optimism). The placebo effect is explored, as is non-suicidal self-injury. Chronic pains are viewed in a context of evolutionary mismatch. The chapter discusses the relationship between pain and depression.