Neutrophil-derived proteases play crucial roles in both chronic and acute inflammatory lung diseases. These enzymes are involved in key neutrophil functions such as NETosis and reactive oxygen species release, and can also cause tissue damage and loss of function when released. While neutrophil serine proteases (NSPs) have been the primary focus of research, clinical trials targeting NSPs have shown mixed results. As a result, research has shifted to less-studied proteases, including cysteine and serine cathepsins, metzincins, and calpains. This review outlines the previous work on NSPs, including the limitations of some inhibitor-based clinical trials, and discusses the growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation. The potential of targeting these less-studied proteases as new therapeutic targets for neutrophil-mediated lung inflammation is highlighted.Neutrophil-derived proteases play crucial roles in both chronic and acute inflammatory lung diseases. These enzymes are involved in key neutrophil functions such as NETosis and reactive oxygen species release, and can also cause tissue damage and loss of function when released. While neutrophil serine proteases (NSPs) have been the primary focus of research, clinical trials targeting NSPs have shown mixed results. As a result, research has shifted to less-studied proteases, including cysteine and serine cathepsins, metzincins, and calpains. This review outlines the previous work on NSPs, including the limitations of some inhibitor-based clinical trials, and discusses the growing understanding of other proteases involved in neutrophil function and neutrophilic lung inflammation. The potential of targeting these less-studied proteases as new therapeutic targets for neutrophil-mediated lung inflammation is highlighted.