The selection of chemotherapy drugs is based on the cytotoxicity to specific tumour cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumour, and cellular evolution. Much progress in the understanding of tumour cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identiﬁcation and characterisation of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difﬁcult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efﬁcacy of chemotherapy against tumours by protecting normal cells and tissues and possibly by diminishing multi-drug resistance in malignant cells.