Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. The B7 family antigens, such as PD-1 and its receptor B7-H1 (PD-L1), are considered therapeutic targets in NSCLC. However, little is known about the significance of other B7 family members. In this study, we determine the expression level of B7-H3 protein as a new B7 family protein in cell lines and tumor tissues from NSCLC patients by immunohistochemistry and quantitative RT-PCR. By screening in a phage displaying human antibody library, we have identified fully human antibodies specific for B7-H3 antigen. To explore B7-H3 as a potential target in NSCLC, two forms of antibody therapeutics, chimeric antigen receptor (CAR) T cells and bispecific killer cell engager (BiKE) based on one anti-B7-H3 antibody have been developed. As results, CAR T cells targeting B7-H3 demonstrated the cytotoxicity against NSCLC cells in vitro and in vivo. Meanwhile, BiKE treatment was demonstrated to significantly inhibit cell growth by inducing natural killer cells. The cytotoxicity of two agents will be further investigated in the PDX mouse models. This study suggests B7-H3 as a promising therapeutics target in NSCLC.