Most of the FDA-approved therapeutic monoclonal antibodies are full-size IgG molecules with a molecular weight of about 150 kDa. A major problem for such large molecules is their poor penetration into tissues (e.g., solid tumors) and poor or absent binding to regions on the surface of some molecules (e.g., on the HIV envelope glycoprotein) which are fully accessible only by molecules of smaller size. Therefore, much work especially during the last decade has been aimed at developing novel scaffolds of much smaller size and high stability. Immunoglobulin-based scaffolds including Fab (∼50 kD), ScFv (∼30 kD), and VH domain (termed domain antibody, dAb) (∼15 kD) have been well established. Recently, a new scaffold based on human IgG1 CH2 domain (∼15 kD) was also proposed (termed nanoantibody, nAb). Binders based on a CH2 scaffold could also confer some effector functions. Here, we describe the design, expression, purification, and characterization of engineered CH2 and VH domains.