Mathematical models of tumor size (TS) dynamics and tumor growth inhibition (TGI) need to place more emphasis on resistance development, given its relevant implications for clinical outcomes. A deeper understanding of the underlying processes, and effective data integration at different complexity levels, can foster the incorporation of new mechanistic aspects into modeling approaches, improving anticancer drug effect prediction. As such, we propose a general framework for developing future semi-mechanistic TS/TGI models of drug resistance.