Oxygen isotope paleotemperature studies of the Mesozoic and Paleozoic are based mainly on conodonts, belemnite guards, and brachiopod shells—material resistant to diagenesis and generally precipitated in oxygen isotope equilibrium with ambient water. The greatest obstacle to accurate oxygen isotope paleothermometry in deep time is uncertainty in the oxygen isotopic composition of the ambient seawater. The second greatest obstacle is fossil diagenesis. Useful application of the oxygen isotope method to brachiopod shells requires extreme care in sample screening and analyses, and is best done with scanning-electron microscopy, and petrographic and cathodoluminescence microscopy, and trace-element analysis. Correct interpretation of oxygen isotope data is greatly aided by thorough understanding of the paleolatitude, paleoecology, and depositional environment of the samples. The oxygen isotope record for the Triassic, based on brachiopod shells, is too sparse to show any distinct isotopic features. Jurassic and Early Cretaceous δ18O records, based on belemnites, show a Toarcian (Jurassic) decline (warming), a Callovian-Oxfordian acme, and an Early Cretaceous increase (cooling) to a Valanginian-Hauterivian maximum, followed by a decline (warming) to a middle Barremian minimum. Deep-time applications to oxygen isotope thermometry provide evidence for cooling and glaciation in the Ordovician, Carboniferous, and Permian. The δ18O values from Silurian and Devonian brachiopod shells and conodonts average lower than those of the remaining Phanerozoic because of the absence of continental glaciers and possibly higher temperatures (~37°?), although slightly lower (≤2%o) seawater δ18O cannot be ruled out. The hypothesis of high temperatures in the early Paleozoic implies a relatively constant hydrospheric δ18O, which is supported by clumped isotope paleotemperatures. However, more research is needed to develop methods for evaluating clumped isotope reordering in fossils. Ongoing and future research in oxygen isotope and clumped isotope thermometry hold the promise of resolving deep-time temperatures, seawater δ18O, and salinity with heretofore unavailable accuracy (±2°, ±0.4%o, and ±2 psu), providing the environmental setting for the evolution of metazoan life on Earth.