The NF-kappaB (NF-kappaB) transcription factor-signaling pathway has become a major focus for research aimed at understanding its role in development, maintenance and progression of disease. A large body of recent research suggests inhibition of NF-kappaB blocks inflammation, cancer development and progression, diabetes, stroke, muscle wasting, and other diseases. The enormous potential for the treatment of disease by inhibiting NF-kappaB lead to the development of inhibitory drugs that specifically target this pathway. At the same time offering great clinical potential, inhibition of NF-kappaB in vivo can be detrimental. NF-kappaB controls multiple functions in homeostasis including a functional immune response, cell cycle, and cell death. Genetic studies in mice and analysis of naturally occurring mutations in humans point to specific developmental and immune consequences due to altering NF-kappaB activity. The balance between therapeutic benefit and potential changes in normal cellular function and response during drug induced NF-kappaB inhibition will be one of the challenges in future clinical studies.