In this lecture we summarize some recent work on the understanding of instanton effects in string theories with 16 supersymmetries. In particular, we consider F4 couplings using the duality between the heterotic string on T4 and type IIA on K3 at an orbifold point, as well as higher and lower dimensional versions of this string‐string duality. At the perturbative level a non‐trivial test of the duality, requiring several miraculous identities, is presented by matching a purely one‐loop heterotic amplitude to a purely tree‐level type II result. A wide variety of non‐perturbative effects is shown to occur in this setting, including D‐brane instantons for type IIA on K3 × S1 and NS5‐brane instantons for type IIA on K3 × T2. Moreover, the analysis of the three‐dimensional case, which possesses a non‐perturbative SO(8, 24, Z) U‐duality, reveals the presence of Kaluza‐Klein 5‐brane instanton effects, both on the heterotic and the type II side.