IκB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are two non-canonical IKKs which are involved in interferon regulatory factor (IRF) as well as nuclear factor kappaB (NF-κB) signaling cascades. Both kinases have already been linked to the pathophysiology of several diseases and therefore been suggested as potential promising targets for the development of therapeutic drugs. In this review, we summarize the roles of IKKε and TBK1 in different diseases and outline therapeutic options for modulation of these kinases.