This article highlights a novel strategy for designing molecules with high thermoelectric performance, which are resilient to fluctuations. In laboratory measurements of thermoelectric properties of single-molecule junctions and self-assembled monolayers, fluctuations in frontier orbital energies relative to the Fermi energyE(F)of electrodes are an important factor, which determine average values of transport coefficients, such as the average Seebeck coefficient & x3008;S & x3009;. In a worst-case scenario, where the relative value ofE(F)fluctuates uniformly over the HOMO-LUMO gap, a "worst-case scenario theorem" tells us that the average Seebeck coefficient will vanish unless the transmission coefficient at the LUMO and HOMO resonances take different values. This implies that junction asymmetry is a necessary condition for obtaining non-zero values of & x3008;S & x3009; in the presence of large fluctuations. This conclusion that asymmetry can drive high thermoelectric performance is supported by detailed simulations on 17 molecules using density functional theory. Importantly, junction asymmetry does not imply that the molecules themselves should be asymmetric. We demonstrate that symmetric molecules possessing a localised frontier orbital can achieve even higher thermoelectric performance than asymmetric molecules, because under laboratory conditions of slight symmetry breaking, such orbitals are 'silent' and do not contribute to transport. Consequently, transport is biased towards the nearest "non-silent" frontier orbital and leads to a high ensemble averaged Seebeck coefficient. This effect is demonstrated for a spatially-symmetric 1,2,3-triazole-based molecule, a rotaxane-hexayne macrocycle and a phthalocyanine.