Omar M. Yaghi published the first paper of covalent organic frameworks (COFs) in 2005, reporting a series of 2D COFs. He reported the design and successful synthesis of COFs by condensation reactions of phenyl diboronic acid (CH[B(OH)]) and hexahydroxytriphenylene (CH(OH)). Powder X-ray diffraction studies of the highly crystalline products having empirical formulas (CHBO)·(CH) (COF-1) and CHBO (COF-5) revealed 2-dimensional expanded porous graphitic layers that have either staggered conformation (COF-1) or eclipsed conformation (COF-5). Their crystal structures are entirely held by strong bonds between B, C, and O atoms to form rigid porous architectures with pore sizes ranging from 7 to 27 Angstroms. COF-1 and COF-5 exhibit high thermal stability (to temperatures up to 500 to 600 °C), permanent porosity, and high surface areas (711 and 1590 square meters per gram, respectively). The synthesis of 3D COFs has been hindered by longstanding practical and conceptual challenges until it was first achieved in 2007 by Omar M. Yaghi  
Yaghi is also known for the design and production of a new class of compounds known as zeolitic imidazolate frameworks (ZIFs). MOFs, COFs, ZIFs are noted for their extremely high surface areas ( for MOF-177) and very low crystalline densities ( for COF-108). Yaghi also pioneered molecular weaving, and synthesized the world’s first material woven at the atomic and molecular levels (COF-505).
He has been leading the effort in applying these materials in clean energy technologies including hydrogen and methane storage, carbon dioxide capture and storage, as well as harvesting water from desert air.
According to a Thomson Reuters analysis, Yaghi was the second most cited chemist in the world from 2000–2010.