Drug response prediction at the single cell level is an emerging field of research that aims to improve the efficacy and precision of cancer treatments. Here, we introduce DREEP (Drug Response Estimation from single-cell Expression Profiles), a computational method that leverages publicly available pharmacogenomic screens and functional enrichment analysis to predict single cell drug sensitivity from transcriptomic data. We extensively tested DREEP on several independent single-cell datasets with over 200 cancer cell lines and showed its accuracy and robustness. Additionally, we also applied DREEP to molecularly barcoded breast cancer cells and identified drugs that can selectively target specific cell populations. DREEP provides an in-silico framework to prioritize drugs from single-cell transcriptional profiles of tumours and thus helps in designing personalized treatment strategies and accelerate drug repurposing studies. DREEP is available at https://github.com/gambalab/DREEP.