Tying knots and handwriting constitute basic motor skills associated with the development of a child's conception of spatial relationships (1). For synthetic chemists, molecular knot tying—so-called topological stereochemistry (2)—often requires the slow, deliberate steps of children learning to tie their shoes. On page 783 of this issue, Ponnuswamy et al. report reaction conditions that appear to drive the spontaneous formation of a knotted organic molecule (3). Previous studies from Sanders' group under conditions known as dynamic combinatorial equilibria revealed a preference for the formation of densely packed aggregates, including topologically complex structures, such as catenanes (linked rings) (4). Recently, investigating the early stages of polymerization by disulfide linkage formation, they have found an unexpected product that appears to be a bona fide molecular knot.