Chemical and mechanical fatigue degradation in ceramic materials is generally inconspicuous yet ubiquitous, to the effect that clinical fractures still consist of the main cause of failure in all-ceramic restorations. Implications of this span wide, from a reduced survival prognosis for the affected teeth, including more frequent and increasingly invasive procedural interventions, to the financial burden borne by individuals and health care systems. To suffice as an effective corrective, restoration lifetimes need only to be extended so to outlive the patient. That opens a box of problems from a materials science standpoint, entailing inherent deficiencies of brittle materials to resist mechanical and environmental challenges. Efforts in developing more damage-tolerant and fatigue-resistant restoratives go thus hand in hand with understanding intrinsic mechanisms of crack growth behavior under conditions that simulate the oral environment. Here we developed experiments using size-relevant sharp precracked specimens with controlled size and geometry (truncated semielliptical crack in the surface-crack-in-biaxial-flexure method) to establish a relationship between crack size and strength. The tangent method was used to construct envelopes for the quasi-static resistance curves (R-curves), which served as template for deriving residual cyclic R-curve analogs. By means of experimentally obtained stress–cycle curves, lifetime and fatigue parameters were employed within a mechanistic framework to reveal constitutive toughening mechanisms during subcritical growth under cyclic loading in a wet environment. Using 3 modern dental lithium disilicate glass–ceramics, we demonstrate the extent of R-curve degradation up to a threshold of 10 million cycles (~30 y in service) and draw parallels between the scope of fatigue degradation and the size of the microstructural units responsible for toughening mechanisms in glass–ceramic materials. Our results indicate that larger microstructural elements endow glass–ceramics with a higher reaching quasi-static R-curve at the onset but degrading more rapidly to comparable levels of lithium disilicates having submicrometric and nanometric crystal phases.