Nuclear factor-kappa B (NF-κB) is a transcription factor involved in a wide variety of phenomena including inflammation, immune responses, and cell survival. Abnormal activation of NF-κB occurs in many pathological conditions, such as allergic and auto-inflammatory diseases and malignancies. As a result, the signal-induced NF-κB activation pathway has been extensively studied and revealed to be regulated by ubiquitination. Several types of polyubiquitin chains exist and the type of chain seems to impact how ubiquitinated proteins are regulated. Recently, different types of polyubiquitin chains, including linear (M1) and K11 chains, have been implicated in NF-κB activation. This review discusses existing evidence of the differential roles played by various ubiquitin chains, particularly K63, M1, and K11 chains, in NF-κB activation.