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The envelopes of Red Supergiants (RSGs) have a unique chemical environment not seen in other types of stars. They foster an oxygen-rich synthesis but are tempered by sporadic and chaotic mass loss, which distorts the envelope and creates complex outflow sub-structures consisting of knots, clumps, and arcs. Near the stellar photosphere, molecules and grains form under approximate LTE conditions, as predicted by chemical models. However, the complicated outflows appear to have distinct chemistries generated by shocks and dust destruction. Various RSG envelopes have been probed for their molecular content, mostly by radio and millimeter observations; however, VY Canis Majoris (VY CMa) and NML Cygni (NML Cyg) display the highest chemical complexity, and also the most complicated envelope structure. Thus far, over 29 different molecules have been identified in the envelopes of RSGs. Some molecules are common for circumstellar gas, including CO, SiO, HCN and H2O, which have abundances of ∼10−6–10−4, relative to H2. More exotic oxides have additionally been discovered, such as AlO, AlOH, PO, TiO2, and VO, with abundances of ∼10−9–10−7. RSG shells support intricate maser emission in OH, H2O and SiO, as well. Studies of isotope ratios in molecules suggest dredge-up at least into the H-burning shell, but further exploration is needed.