The mediation of knowledge by signs, belief systems, and practices leads to some of the problems of modern rationalism. This chapter discusses the failure of Cartesian epistemology, the problem of relativism, and the science/metaphysics/religion debates. These discussions and their results offer clues for a logic of worldviews. Cartesian or foundational epistemology faces problems. Knowledge and belief systems are intertwined in the practices of responding to reality. Justifying criteria requires metatheoretical reasoning, as otherwise one cannot contrast criteria with the world. The Gettier problem arises when the evidence leads to a practice that picks out the wrong witness individuals for the belief. Relativism became a topic of discussion in the 1990s and 2000s in debates that split knowledge between the object and the subject. Knowledge is instead mediated by practices, which connect it with reality and can be compared without a collapse into an “anything goes” relativism. The science/religion and science/metaphysics debates show a similar logic because worldviews form metatheories for knowledge. Scientism holds science to be the only source of knowledge, nonoverlap theories separate fact and meaning, and partial overlap views hold that worldviews offer starting points for science. Metaphysics and religion give high-level assumptions of the world to guide activities like scientific research.