Could new physics first manifest itself in Higgs self-coupling measurements? In other words, how large could deviations in the Higgs self-coupling be, if other Higgs and electroweak measurements are compatible with Standard Model predictions? Using theoretical arguments supported by concrete models, we derive a bound on the ratio of self-coupling to single-Higgs coupling deviations in ultraviolet completions of the Standard Model where parameters are not fine-tuned. Broadly speaking, a one-loop hierarchy is allowed. We thus stress that self-coupling measurements at the LHC and future colliders probe uncharted parameter space, presenting discovery potential even in the absence of emerging hints in single-Higgs coupling measurements. For instance, if other observables show less than two-sigma deviations by the end of the LHC programme, the Higgs self-coupling deviations could still exceed 200% in the models discussed, without introducing fine-tuning of ultraviolet parameters.