In the present work, urgent issues in the reliability qualification of semiconductor devices are addressed, which particularly affect value chains such as those in the automotive industry. These have particularly high requirements for long lifetime and low failure rates of their products, which are additionally exposed to more extreme operating and environmental conditions than in most other areas of application. In particular, the question arises on how to assess a product or semiconductor technology against the requirement of an application-specific mission profile with multiple non-constant stressors. For this purpose, the behavior of failure distributions under varying and progressive stress loads is investigated and described using cumulative damage models. For the first time, the industry-wide approach of transforming non-constant mission profiles into effective constant stress and test conditions for reliability assessment and qualification can be physically justified and substantiated with measurement data. This stress transformation is exemplified using the time-dependent dielectric breakdown (TDDB) failure mechanism with the two stressors voltage and temperature; and then extended to include the use of multi-dimensional mission profiles and interdependent stressors. These measurements are performed on university metal-oxide-semiconductor (MOS) capacitors as well as on commercially available state-of-the-art transistors. Finally, it is demonstrated that the obtained findings in the field of cumulative damage can be applied to use reliability studies with ramp-stress for acceleration model verification and to determine model parameters with less time and experimental effort