This PhD thesis represents a first milestone in the evaluation of the calendar and cycle degradation mechanisms in long-term application of automotive lithium-ion cells. Within this work the detailed analysis of the degradation mechanisms in function of battery operating conditions has been performed for the first time. It has been shown that the temperature, the state of charge and the depth of discharge are the most crucial parameters. Furthermore a unique approach consisting in a statistical analysis of long-term aged cells by means of XPS depth-profiling has been applied to determine the composition and growth of the solid electrolyte interphase for a large number of different long-term aged cell materials. The evolution of gas is identified as the second major degradation mechanism at high state of charge and especially at high temperature storage/operation. Furthermore, the profound analysis of cells at high state of charge operation using STEM-EELS revealed the intensified dissolution of transition metal from the cathode material. Contrary to literature reports, the major degradation during battery operation under a high depth of discharge is attributed to the cathode particle cracking instead of the accelerated growth of the SEI. In addition, inhomogeneous degradation resulting from enclosed gas, temperature and lithium- concentration gradients is identified as major cause for accelerated loss of cell performance. The identified correlations between operation of the lithium-ion cells, the corresponding electrical data and the data gathered from post-mortem analysis enable a lifetime optimized design of the operation strategy in the application, conceivable enhancement of lifetime >15 years and >300.000 km.