Mutation, Randomness, and Evolution presents a new understanding of how the course of evolution may reflect biases in variation and unites key concerns of molecular and microbial evolution, evo-devo, evolvability, and self-organization by placing these concerns on a solid theoretical and empirical foundation. It situates them within a broader movement away from externalism and towards a focus on the internal details of living systems, including their evolutionary causes and their predictable evolutionary consequences. In the neo-Darwinian theory, by contrast, selection is the potter and variation is the clay: external selection does the important work of evolution, and gets all the credit, while variation merely supplies an abundance of random raw materials. Indeed, one of the meanings of the randomness doctrine is that any peculiarities or tendencies of mutation are ultimately irrelevant. The theory that the course of evolution is determined externally, without any dispositional role for internal factors, was particularly attractive before the molecular revolution, when biologists had little systematic knowledge of internal factors. Today, scientists are deeply immersed in the molecular, genetic, and developmental details of life. The potential for a new understanding of the role of these internal factors rests on the recognition that the introduction process is a distinctive kind of cause, not the same thing (conceptually, historically, or theoretically) as the classical “force” of mutation, but with different implications, including the ability to impose biases on adaptive evolution. This predicted influence is verified by recent evidence from episodes of adaptation traced to the molecular level.