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Knotting in proteins was once considered exceedingly rare. However, systematic analyses of solved protein structures over the last two decades have demonstrated the existence of many deeply knotted proteins, and researchers now hypothesize that the knotting presents some functional or evolutionary advantage for those proteins. Unfortunately, little is known about how proteins fold into knotted configurations. In this talk, we approach this problem from a theoretical point of view, using topological techniques. In particular, based on computational and experimental evidence, we propose a new theoretical pathway for proteins to form knots. We then use topological techniques to compare the configurations obtained from the theoretical pathways with known configurations of actual proteins. This is joint work with Erica Flapan and Adam He.