The inhibitory CD200–CD200 receptor (CD200R) interaction is essential to prevent massive inflammatory responses and immune pathology during microbial infection. Since CD200 expression on human malignancies is associated with tumor progression, CD200 blocking antibodies are currently tested in clinical trials to boost anti-tumor responses. Here we discuss that CD200-mediated suppression of anti-tumor responses may not only be mediated by the tumor itself, but also by CD200 expressed on healthy tissue. However, in cancers that benefit from inflammation, the blockade of CD200 could result in enhanced tumor growth. We conclude that CD200 blockade forms a potential therapeutic option to strengthen anti-tumor responses which is not restricted to treatment of CD200 expressing tumors.