Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPalpha interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRPalpha interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cell-mediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy. The latter may be SIRPalpha-dependent or SIRPalpha-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies.