Nickel-base superalloys are primarily used as components in jet engines and land-based turbines. While compositionally complex, they are microstructurally simple, consisting of small (50–1000 nm diameter), ordered, coherent Ni 3 (Al,Ti)-type L1 2 or Ni 3 Nb-type DO 22 precipitates (called γ ′ and γ ′′ , respectively) embedded in an FCC substitutional solid solution consisting primarily of Ni and other elements which confer desired properties depending upon the application. The grain size may vary from as small as 2 μm for powder metallurgy alloys used in discs to single crystals the actual size of the component for turbine blades. The fatigue behaviour depends upon the microstructure, deformation mode, environment and cycle time. In many cases, it can be controlled or modified through small changes in composition which may dramatically change the mechanism of damage accumulation and the fatigue life. In this paper, the fundamental microstructural, compositional, environmental and deformation mode factors which affect fatigue behaviour are critically reviewed. Connections are made across a range of studies to provide more insight. Modern approaches are pointed out in which the wealth of available microstructural, deformation and damage information is used for computerized life prediction. The paper ends with a discussion of the very important and highly practical subject of thermo-mechanical fatigue (TMF). It is shown that physics-based modelling leads to significantly improved life prediction. Suggestions are made for moving forward on the critical subject of TMF life prediction in notched components.