Lefty (left-right determination factors) are a class of proteins that are closely related members of the TGF-beta superfamily of growth factors. Lefty-1 is a regulatory gene that plays a vital role in the determination of the left-right internal asymmetry observed in mammals. The lefty-1 protein works in tandem with two other genes: lefty-2 and nodal. As the primitive node migrates towards the cranial end of the embryo during development, its cilia preferentially sling lefty-2 and nodal towards the left side of the embryo. These two genes encode for “leftness”, and initiate the formation of the heart, spleen, and other internal organs that are found on the left side in a typical human being. Lefty-1 protein can be viewed as a barrier between the left and right portions of the embryo that prevents the diffusion of lefty-2 and nodal to the right side. This ensures that the left-determining molecules are confined to their correct developmental domain. A variety of defects were observed in mice that had lefty-1 deleted, including left pulmonary isomerism, situs inversus, and atrial septal defect. The high incidence of left pulmonary isomerism in the knockout mice indicates that lefty-1 itself is not involved in encoding for leftness, but simply ensures the correct compartmentation of the left-determining molecules. In the absence of the lefty-1 barrier, lefty-2 and nodal are free to diffuse to the right side and initiate the development of a left lung that was meant to be limited to the left side of the thoracic cavity.