The new germacrane derivatives ketopelenolides C and D have been isolated from great mugwort (Artemisia arborescens). Their stereostructure elucidation exemplifies some of the most common pitfalls facing the configurational assignment of medium-sized polyfunctionalized compounds. It was established through a combined strategy including chemical derivatization, NMR data analysis, molecular modeling, and quantum-mechanical calculations including a comparison between experimental 13C NMR data and a Boltzmann-weighted average of DFT-calculated 13C NMR chemical shifts.