Integral membrane proteins contain a hydrophobic transmembrane domain and mainly locate in the plasma membrane lipid bilayer. The receptor tyrosine kinases (RTK) of the epidermal growth factor receptor (EGFR) superfamily, including ErbB-1, ErbB-2, ErbB-3, and ErbB-4, constitute an important group of such membrane proteins, which have a profound impact on cancer initiation, progression, and patient outcome. Although studies of their functions have conventionally focused on their membrane-associated forms, documented observations of the presence of these membrane receptors and their functioning partners in the nucleus have reshaped the intracellular geography and highlight the need to modify the central dogma. The ErbB proteins in the membrane can translocate to the nucleus through different mechanisms. Nuclear RTKs regulate a variety of cellular functions, such as cell proliferation, DNA damage repair, and signal transduction, both in normal tissues and in human cancer cell. In addition, they play important roles in determining cancer response to cancer therapy. Nuclear presence of these ErbB proteins is emerging as an important marker in human cancers. An integrated picture of the RTK-centered signaling transduction network extending from the membrane-cytoplasm boundary to the nuclear compartment is looming in the foreseeable horizon for clinical application.