In this chapter we compare and contrast chemical and photochemical pathways for mass-independent fractionation (MIF) of oxygen isotopes in the solar nebula. We begin by assessing the galactic evolution model for oxygen isotope variation in the Solar System in order to compare the predictions of a leading nucleosynthetic model with those of the chemical models. There are two fundamentally different classes of possible chemical mechanisms for mass-independent oxygen isotope fractionation in the early Solar System. One is symmetry-induced intramolecular vibrational disequilibrium of vibrationally excited reactant oxygen-bearing molecules. The other is isotope selective photodissociation of CO coupled with self-shielding and formation of H2O. Symmetry-induced fractionation is an experimentally verified process with solid theoretical foundations. It is observed to occur in Earth’s atmosphere. It could have resulted in preservation of oxygen MIF effects only if mediated by dust grain surfaces. CO self-shielding is an attractive hypothesis for the origin of mass-independent oxygen isotope fractionation in the early Solar System because it appeals to a process that apparently occurs in the interstellar medium, but it lacks experimental verification. Three astrophysical settings for CO self-shielding are proposed as sites for generating Δ17O variability in the early Solar System. One is the inner annulus of the protostellar disk at relatively high temperature. Another is the surface of the disk high above the midplane where light from the central star grazes the gas and dust of the disk, resulting in a zone of active CO predissociation and self-shielding. Interstellar light illuminating the disk at high incident angles causes a similar horizon of CO photodestruction. Variations in 16O could also have been inherited from self-shielding by CO in the molecular cloud that gave rise to the protosun. The overall consequence of CO self-shielding is conversion of CO gas to 16O-poor H2O. A key difference between galactic evolution, chemically-induced MIF effects, and CO self-shielding is the predicted relative oxygen isotopic compositions of primeval dust and the Sun. Therefore, the oxygen isotopic composition of the Sun will be a crucial arbiter that may permit us to narrow the list of possible origins for oxygen MIF in the early Solar System.