The understanding of conditioned co-arising is central to Buddhist practice and development. This chapter presents the principle of conditionality, which can be applied to all processes, events, and things, physical or mental, in the universe. Besides explaining the origin of dukkha, the conditioned co-arising formula also explains karma, rebirth, and the functioning of personality, all without the need to invoke a permanent self. Buddhism sees the basic root of the pain and stress of life as spiritual ignorance, rather than sin. The between-lives period has three phases: inclining to a further rebirth, seeking it here and there, and falling from one's previous identity into a new rebirth. In the Mahāyāna movement, various uses were made of the conditioned co-arising. As a general point on conditioned co-arising, it should be noted that it presents a “middle” way of understanding that echoes the Buddhist path as a “middle way” of practice.