Calreticulin, a calcium-binding protein that is highly conserved in its multiple functions, is present in a wide spectrum of subcellular compartments in virtually every cell of higher organisms. In this article, we propose a dual role for parasite calreticulin, with emphasis on the Trypanosoma cruzi model. By modulating the vertebrate complement system, calreticulin might provide the parasite with an effective immune-escape mechanism. Alternatively, by inhibiting angiogenesis, the parasite molecule might protect the host from ongoing neoplasic aggressions. Many questions are still unanswered, particularly those regarding the consequences that these interactions could have in vivo for both the parasite and the host.