Stimulation with diverse agents activates the NF-kappaB (nuclear factor kappaB) transcription factor, affecting inflammatory and immune responses, proliferation, differentiation, apoptosis and tumourigenesis. Determining how NF-kappaB elicits such distinct responses is essential to understanding NF-kappaB function in diseased tissues. Recent developments illustrating that post-translational modification of NF-kappaB subunits influences their nuclear role are discussed. These observations suggest that diagnosis and new therapies based on reprogramming NF-kappaB activity could be more efficient than total NF-kappaB inhibition.