Among cancer therapies relying on the defects in DNA repair mechanisms, the platinum agents (e.g. cisplatin or carboplatin) are most widely used. Despite being effective in majority of patients, the tumor often relapses, and these originally sensitive cancers acquire resistance towards platinum-based drugs. The mechanism of resistance development is not well understood and there is no clinical approach to prevent or diagnose it. The main aim of this study was to identify DNA repair pathways involved in drug sensitivity and resistance by RNAi knockdown and CRISPR/Cas9 knockout screenings. The authors tested a library of genes involved in different DNA repair pathways in the hTERT RPE-1 cell line. Silencing by RNAi and CRISPR-based knockout of the target genes were followed with drug treatments to identify repair pathway crosstalks. In conclusion, the comprehensive analysis of DNA repair pathway efficiencies, preferably achieved by cancer whole-genome sequencing could provide a diagnostic tool for treatment selection and could be applied in day-to-day cancer diagnostics.