In 1963, he joined Arizona State University where he is now Regents’ Professor of Chemistry. Early research work was devoted to the study of defects, conductivity and diffusion in solids, particularly solid electrolytes.  His more recent research is devoted to the theory of periodic structures (nets (periodic graph (crystallography)), tilings (periodic tessellations, and weavings (a higher dimensional version of Braid theory)) relevant to development of a taxonomy of such structures and its application to materials design and description.  In collaboration with Omar Yaghi, O’Keeffe developed reticular chemistry, a new branch of chemistry that links molecular fragments of well-defined shapes with strong bonds to build symmetrical open structures such as metal-organic frameworks (MOFs), zeolitic imidazolate frameworks (ZIFs), and covalent organic frameworks (COFs)  Together with Olaf Delgado-Friedrichs, he has developed the Reticular Chemistry Structure Resource (RCSR) a compendium of structures relevant to design of materials on the molecular level. O'Keeffe has published three books, including one of the standard monographs on periodic structures, and more than 300 refereed papers. His work is highly cited (over 100,000 citations and h index over 100), and he was third in the Clarivate#Highly Cited Researchers list of Top 100 Chemists, 2000-2010