Neutrophils are the most abundant circulating leukocytes, being the first line of defence against bacterial and fungal infections. However, neutrophils also contribute to tissue damage during various autoimmune and inflammatory diseases, and play important roles in cancer progression. The intimate but complex involvement of neutrophils in various diseases makes them exciting targets for therapeutic intervention but also necessitates differentiation of beneficial responses from potentially detrimental side effects. A variety of approaches to therapeutically target neutrophils have emerged, including strategies to enhance, inhibit or restore neutrophil function, with several agents entering clinical trials. However, challenges and controversies in the field remain.