The concept of pericyclic reactions and the explanation of their specificity through orbital symmetries introduced a new way of understanding reactions and looking for new ones. One of the 1965 Woodward-Hoffmann communications described "the (as yet unobserved) symmetry-allowed 6 + 4 combination", the prediction of a new field of "higher-order" cycloadditions, involving more than six electrons. Later these authors predicted exo-stereoselectivity for the [6 + 4]-cycloaddition. Chemists rushed to test this prediction (for the most part successfully). For more than half a century, chemists have hunted for additional higher-order cycloadditions. The application of catalysis within organic chemistry allows the accomplishment of previously unattainable reactions, including higher-order cycloadditions. The many examples of [8 + 2], [6 + 4], and cycloadditions of even higher electron-counts discovered since the Woodward-Hoffmann rules were introduced illustrate the difficulty in predicting which of these transformations will occur when two highly unsaturated molecules react. Periselectivity has been a challenge, and the development of enantioselective variants has been elusive. While progress was made, the rise of organocatalysis in asymmetric synthesis has led to a surge of interest in stereoselective versions of higher-order cycloadditions. Through organocatalytic activation of conjugated cyclic polyenes and heteroaromatic compounds, asymmetric [8 + 2]-, [6 + 4]-, and [10 + 4]-cycloadditions have been realized by our groups. In this century, [6 + 4]-cycloadditions have been found also to occur in enzyme-catalyzed reactions for the biosynthesis of spinosyn A, heronamide, and streptoseomycin natural products. A whole new class of enzymes, the pericyclases that catalyze pericyclic reactions, has been discovered. A remarkable aspect of these recent developments is the cross-disciplinary research involved: from organic synthesis to computational studies integrated with experimental studies of reaction mechanisms, intermediates, and dynamics, to understanding mechanisms of enzyme catalysis and engineering of enzymes. This Account describes how our groups have been involved in the expansion of the higher-order cycloaddition frontiers. We describe both the history and recent progress in higher-order cycloadditions, and how these advances have been made by our collaborative experimental and computational studies. Progress in asymmetric organocatalysis, incorporating enantioselective higher-order cycloadditions in organic synthesis, and the stereoselective synthesis of important scaffolds will be highlighted. Experimental progress and computational modeling with density functional theory (DFT) has identified ambimodal cycloaddition pathways and led to the realization that multiple products of pericyclic reactions are linked by common transition states. Molecular dynamic simulations have provided fundamental understanding of factors controlling periselectivity and have led to discoveries of a group of enzymes, the pericyclases, which catalyze pericyclic reactions such as [6 + 4]-cycloadditions.