Even though the motivation to feel worthy, to be respected, and to matter to others has been identified for centuries by scholars, the antecedents, consequences, and conditions of its activation have not been systematically analyzed or integrated. The purpose of this article is to offer such an integration. We feature a motivational construct, the quest for significance, defined as the need to have social worth. This need is typically fulfilled by a sense of measuring up to the values one shares with significant others. Our significance-quest theory (SQT) assumes that the need for significance is universal, whereas the means of satisfying it depend on the sociocultural context in which one’s values are embedded. Those means are identified in a narrative supported and validated by one’s network, or reference group. The quest for significance is activated by significance loss and/or the opportunity for significance gain. It motivates behavior that aims to affirm, realize, and/or show commitment to an important value. The SQT is consistent with large bodies of prior research and supported by novel studies in multiple laboratory and field settings. It transcends prior understandings and offers guidance for further study of this essential human motivation.