It is well known that non-canonical IκB kinases (IKK), IKKϵ and Tank-binding kinase 1 (TBK1), play a key role in anti-viral responses. Interestingly, they have recently emerged as novel survival kinases in several human cancers including lung cancer, given their roles in maintaining cancer cell survival and promoting oncogenic transformation. However, the molecular mechanisms by which IKKϵ/TBK1 are activated and IKKϵ/TBK1 mediate survival signal in cancer cells are still controversial. This article will briefly describe signaling pathways mediated by these non-canonical IKKs, especially focusing in lung cancer, and discuss their potential as molecular targets for lung cancer treatment.