Monoclonal antibody (mAb) targeting to tumor antigen is an important therapeutic approach for the treatment of a variety of cancers. Both positive and negative co-stimulatory pathways are critical components for the control and fine-tuning fo immune responses and recently mAb targeting of lymphocyte co-stimulatory pathways has been investigated. With the development of agonistic and antagonistic mAbs, both positive and negative pathways can be regulated and the potent therapeutic efficacy of this method has been demonstrated in experimental models. With high affinity and selectivity, as well as humanization technology for mAbs, there is little doubt that this new approach alone, or in combination with other therapeutic modalities, will play an important role in immunotherapy for cancers in the near future.