The mitogen-inducible gene-6 (Mig-6) is an immediate early response gene encoding a nonkinase scaffolding adaptor protein. Mig-6 gene expression can be rapidly and robustly induced under both normal and pathological scenarios by factors including hormones, growth factors, and stresses. However, the precise role of Mig-6 has virtually been a mystery until recently, when we and others discovered that Mig-6 may play important roles in regulating stress response, maintaining homeostasis in tissues like joints or cardiac muscle, and functioning as a tumor suppressor. The discovery that Mig-6 acts as a negative feedback inhibitor of EGF receptor signaling through a direct, physical interaction with the EGF receptor opens a door for understanding the mechanism underlying Mig-6 function. Yet how Mig-6 fine tunes or integrates signal transduction in many pathophysiological situations remains to be determined. Here we will highlight recent discoveries on the role of Mig-6 in stress response, tissue homeostasis, and cancer development; review the transcriptional regulation of Mig-6 expression; share insight into its mechanism in regulating signal transduction; and discuss the paradox of its action modes under different pathophysiological conditions.