The article reviews the mechanisms and clinical applications of targeting the NF-κB pathway in diseases. NF-κB consists of canonical and non-canonical pathways, both of which play crucial roles in immune responses and inflammatory diseases. The canonical NF-κB pathway is activated by various stimuli, leading to the rapid and transient transcriptional activity of proinflammatory genes. The non-canonical NF-κB pathway, activated through TNF receptor superfamily members, is slower but more persistent due to its involvement in protein synthesis. Ubiquitination plays a vital role in regulating the activation of both pathways. Dysregulation of NF-κB activity is linked to inflammation-related diseases and cancers, making it a potential therapeutic target. The review discusses the activation mechanisms of both pathways, their regulation, and their involvement in immune responses. It also explores the role of NF-κB in cancer, highlighting its tumor-promoting effects and the potential of targeting NF-κB for cancer therapy. The article concludes by discussing the regulation of the non-canonical NF-κB pathway, emphasizing the role of NIK and IKKα in p100 processing and the involvement of TRAF-dependent and TRAF-independent mechanisms in NIK degradation.The article reviews the mechanisms and clinical applications of targeting the NF-κB pathway in diseases. NF-κB consists of canonical and non-canonical pathways, both of which play crucial roles in immune responses and inflammatory diseases. The canonical NF-κB pathway is activated by various stimuli, leading to the rapid and transient transcriptional activity of proinflammatory genes. The non-canonical NF-κB pathway, activated through TNF receptor superfamily members, is slower but more persistent due to its involvement in protein synthesis. Ubiquitination plays a vital role in regulating the activation of both pathways. Dysregulation of NF-κB activity is linked to inflammation-related diseases and cancers, making it a potential therapeutic target. The review discusses the activation mechanisms of both pathways, their regulation, and their involvement in immune responses. It also explores the role of NF-κB in cancer, highlighting its tumor-promoting effects and the potential of targeting NF-κB for cancer therapy. The article concludes by discussing the regulation of the non-canonical NF-κB pathway, emphasizing the role of NIK and IKKα in p100 processing and the involvement of TRAF-dependent and TRAF-independent mechanisms in NIK degradation.