Macrophages are crucial orchestrators of host defence and tissue homeostasis. Macrophages are heterogeneous and plastic cells that in response to different microenvironmental signals can mount a broad spectrum of different programs of polarized activation. In different pathological contexts including cancer and infectious diseases, macrophages diversity and plasticity may act as a double-edged sword. The elucidation of the molecular mechanisms underlying macrophages recruitment and functional activation allows the identification of valuable targets for the development of innovative therapeutic approaches.