A digital microfluidic (DMF) system was developed for drug screening using primary tumor cells to enable precision medicine. The system allows for the parallel screening of three drugs on a 4×4 cm² chip within a 23×16×3.5 cm³ device. The system uses smart control logic to increase throughput and reduce footprint. It was validated using an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs effective on individual primary tumor cells. Mice treated with ineffective drugs showed similar results to controls. The effective drug identified on-chip matched the absence of mutations in related genes, validating the protocol. The system offers a cost-effective, portable solution for drug screening, with a small footprint and high throughput. It can be used in animal facilities or clinics to handle limited primary tumor cells. The system was tested on liver cancer samples, showing consistent results with exome sequencing data. The system allows for the direct screening of primary tumor cells, providing reliable information for precision medicine. The system was also tested on liver cancer patients, showing that the effective drug identified on-chip delayed tumor recurrence in one patient. The system has potential for future improvements, including the development of a more reliable automatic control system and the use of 3D culture techniques for better tumor modeling. The system is a promising tool for precision medicine in cancer treatment and other diseases.A digital microfluidic (DMF) system was developed for drug screening using primary tumor cells to enable precision medicine. The system allows for the parallel screening of three drugs on a 4×4 cm² chip within a 23×16×3.5 cm³ device. The system uses smart control logic to increase throughput and reduce footprint. It was validated using an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs effective on individual primary tumor cells. Mice treated with ineffective drugs showed similar results to controls. The effective drug identified on-chip matched the absence of mutations in related genes, validating the protocol. The system offers a cost-effective, portable solution for drug screening, with a small footprint and high throughput. It can be used in animal facilities or clinics to handle limited primary tumor cells. The system was tested on liver cancer samples, showing consistent results with exome sequencing data. The system allows for the direct screening of primary tumor cells, providing reliable information for precision medicine. The system was also tested on liver cancer patients, showing that the effective drug identified on-chip delayed tumor recurrence in one patient. The system has potential for future improvements, including the development of a more reliable automatic control system and the use of 3D culture techniques for better tumor modeling. The system is a promising tool for precision medicine in cancer treatment and other diseases.