Approximately 85% of lung cancer cases are recognized as non-small cell lung cancer (NSCLC) with a perilous (13-17%) 5-year survival in Europe and the USA. Although tobacco smoking has consistently emerged as the leading cause of NSCLC complications, its consequences are distinctly manifest with respect to sex bias, due to differential gene and sex hormone expression. Estrogen related receptor α (ERRα), a member of the nuclear orphan receptor superfamily is normally expressed in the lungs, and activates various nuclear genes without binding to the ligands, such as estrogens. In NSCLC ERRα expression is significantly higher compared with healthy individuals. It is well established ERα and ERβ' have 93% and 60% identity in the DNA and ligand binding domains, respectively. ERα and ERRα have 69% (70% with ERRα-1) and 34% (35% with ERRα-1) identity, respectively; ERRα and ERRβ' have 92 and 61% identity, respectively. However, whether there is distinctive ERRα interaction with mammalian estrogens or concurrent involvement in non-ER signalling pathway activation is not known. Relevant to NSCLC, ERRα promotes proliferation, invasion and migration by silencing the tumor suppressor proteins p53 and pRB, and accelerates G-M transition during cell division. Epithelial to mesenchymal transition (EMT) and activation of Slug (an EMT associated transcription factor) are the prominent mechanisms by which ERRα activates NSCLC metastasis. Based on these observations, the present article focuses on the feasibility of antiERRα therapy alone and in combination with antiER as a therapeutic strategy for NSCLC complications.