The effects of furan and maleimide substitution on the dynamic reversibility of their Diels-Alder reactivity have been investigated computationally and by (1)H NMR spectroscopy. Furan and furan derivatives bearing methoxy, methyl, or formyl groups at their 2- or 3-positions were investigated with maleimide and maleimide derivatives bearing N-methyl, N-allyl, and N-phenyl substituents. Computational predictions indicate that electronic and regiochemical effects of furan substitution significantly influence their Diels-Alder reactivity with maleimide, with reaction free energies of exo adduct formation ranging from ΔG = -9.4 to 0.9 kcal/mol and transition state barriers to exo adduct formation ranging from ΔG(‡) = 18.9 to 25.6 kcal/mol. Much less variation was observed for the reactivity of N-substituted maleimide derivatives and furan, with reaction and transition state free energies each falling within a range of 1.1 kcal/mol. Dynamic exchange experiments monitored by (1)H NMR spectroscopy support computational predictions. The results indicate the reactivity and reversibility of furan-maleimide cycloadditions can be tuned significantly through the addition of appropriate substituents and have implications in the use of furan and maleimide derivatives in the construction of thermally responsive organic materials.