Macrophages sustain tumour progression by facilitating angiogenesis, promoting immunosuppression, and enhancing cancer cell invasion and metastasis. They also modulate tumour response to anti-cancer therapy in pre-clinical models. This knowledge has motivated the development of agents that target tumour-associated macrophages (TAMs), some of which have been investigated in early clinical trials. Here, we provide a comprehensive overview of the biology and therapeutic targeting of TAMs, highlighting opportunities, setbacks, and new challenges that have emerged after a decade of intense translational and clinical research into these multifaceted immune cells. (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.