Hydroelectric runners are subjected to magnified structural loads during partial-load operation and start/stop cycles. The integration of massive amounts of intermittent renewable energy sources compels conventional electricity providers like hydropower to increase their operational flexibility, leading to a more frequent occurrence of harmful operating conditions. These trends must be considered in the fatigue design of hydromechanical components. This paper aims at providing new insights to improve the reliability of stress-life based fatigue design methods for hydroelectric runners operating under flexible operating schemes. Detailed numerical stress and fatigue analyses of a 5 MW pump-turbine unit with variable speed are presented and compared to experimental data in a wide range of turbine operations. Stresses in the runner structure are numerically evaluated using CFD and one-way coupled FSI simulations. The multiaxiality of the stress state and the suitability of popular equivalent stress measures for stress-life fatigue models are discussed. A critical plane method is adopted to overcome limitations of conventional equivalent stresses and to improve reliability in case of multiaxial loading. Then, a quasi-steady fatigue modeling approach that separates High Cycle Fatigue and Low Cycle Fatigue contributions is proposed to predict partial damages induced by arbitrary operating trajectories. In the end, the proposed fatigue modeling approach is applied to different turbine start-up sequences and validated by experimental results.