Targeting the non-transformed stromal components in the tumour microenvironment (TME) has become clinically attractive in cancer treatment over the last few decades. On this basis, anti-angiogenic therapy that inhibits new blood vessel sprouting has been developed and integrated in modern cancer treatment regimens. However, tumour response to anti-angiogenic therapy is complex due to its heterogeneous and dynamic nature. In addition to cancer cells, the TME is composed of various stromal cells that play an important role in modifying the tumour response, e.g., assisting development of resistance to anti-angiogenic therapy. Moreover, the unselective large-scale application of anti-angiogenic therapy in clinical oncology, resulting in overall modest patient benefit and various resistance patterns, has underscored a pressing need for rational use of these expensive agents. Attempting to address the challenges in recognising the exact role of each tumour component and thus the mechanisms of resistance to anti-angiogenic therapy, we first separate stromal blood endothelial cells (ECs) as a research focus to investigate their role in the altered tumour response. Large-scale functional genetic screening using CRISPR-Cas9 technology that enables systemic perturbation of gene function in ECs will be applied to identify important regulatory signalling hubs implicated in the altered EC response to treatment (e.g. ECs become resistant or sensitive to treatment). Insight into the EC biology in cancer and treatment could provide a better understanding of complex underlying molecular and cellular dynamics provoked by anti-angiogenic treatment within the TME, which holds high potential biomarker and therapeutic value for rational medicine use.