Neutrophil-derived proteases play a critical role in the pathology of both chronic and acute inflammatory lung diseases. These enzymes are involved in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release, and can cause tissue damage and loss of function when released. Historically, neutrophil serine proteases (NSPs), including neutrophil elastase (NE), cathepsin G (CTSG), and proteinase 3 (PR3), have been the focus of research. However, clinical trials targeting NSPs have shown mixed results, prompting a shift towards less studied proteases, such as cysteine and serine cathepsins, metzincins, and calpains. This review discusses the roles of these proteases in neutrophil function and lung inflammation, highlighting their potential as new therapeutic targets. NSPs, particularly NE, are involved in various lung diseases, but their inhibition has been limited by variable efficacy and side effects. In contrast, inhibitors of cathepsin C (CTSC), such as Brensocatib, have shown promising results in some trials. Other proteases, including cathepsin S (CTSS), calpains, and metzincin proteases, also play significant roles in lung inflammation and neutrophil function. The review emphasizes the need for further research into these proteases to develop more effective treatments for lung diseases.Neutrophil-derived proteases play a critical role in the pathology of both chronic and acute inflammatory lung diseases. These enzymes are involved in key neutrophil functions, such as neutrophil extracellular trap formation and reactive oxygen species release, and can cause tissue damage and loss of function when released. Historically, neutrophil serine proteases (NSPs), including neutrophil elastase (NE), cathepsin G (CTSG), and proteinase 3 (PR3), have been the focus of research. However, clinical trials targeting NSPs have shown mixed results, prompting a shift towards less studied proteases, such as cysteine and serine cathepsins, metzincins, and calpains. This review discusses the roles of these proteases in neutrophil function and lung inflammation, highlighting their potential as new therapeutic targets. NSPs, particularly NE, are involved in various lung diseases, but their inhibition has been limited by variable efficacy and side effects. In contrast, inhibitors of cathepsin C (CTSC), such as Brensocatib, have shown promising results in some trials. Other proteases, including cathepsin S (CTSS), calpains, and metzincin proteases, also play significant roles in lung inflammation and neutrophil function. The review emphasizes the need for further research into these proteases to develop more effective treatments for lung diseases.