Oncogenic proteins cooperate to promote tumor development and progression by sustaining cell proliferation, survival and invasiveness. Constitutive epidermal growth factor receptor (EGFR) and nuclear factor κb (NF-κB) activities are seen in multiple solid tumors and combine to provide oncogenic signals to cancer cells. Understanding how these oncogenic pathways are connected is crucial, given their role in intrinsic or acquired resistance to targeted anticancer therapies. We review molecular mechanisms by which both EGFR- and NF-κB-dependent pathways establish positive loops to increase their oncogenic potential. We also describe how NF-κB promotes resistance to EGFR inhibitors.