This thesis presents the research of the development, optimization and in-depth validation of personalizable multidrug combinations to treat clear cell renal cell carcinoma. This was done in ccRCC cells sensitive or resistant to sunitinib – a first-line standard of care, using the in-house developed and validated Therapeutically Guided Multidrug Optimization (TGMO) technology and subsequent pre-clinical in vitro methods to establish optimized multidrug combinations (ODC) to effectively and selectively treat ccRCC. It is anticipated that the information provided in these studies will stimulate future in vivo and potential clinical evaluation of optimized multidrug combinations. The techniques used here should guide personalized drug combinations for cancer treatment in the future.