Monoclonal antibodies remain a primary product option for novel cancer treatment. The properties of an antibody are a function of the antigen specificity and constant region incorporated. The rapid advance in molecular understanding of cancer biology and the host–tumor interaction has defined a new range of targets for antibody development. The clinical success of the checkpoint inhibitors has validated immune modulation and mobilization as a therapeutic approach. Solid cancers are distinguished from hematologic malignancies because the solid tumor stroma contains significant tumor promoting and immune dampening elements less prominent in hematologic cancer. This review highlights how engineered monoclonal antibody products are emerging as potential cornerstones of new more personalized cancer treatment paradigms that target both tumor and the stromal environment.