Abstract: Many patients with preneoplastic gammopathy remain clinically stable, in spite of the presence of multiple genomic abnormalities in tumor cells. Our hypothesis is that the development of clinical cancer depends not just on the genomic changes in tumor cells, but also their interactions with the host‐tumor microenvironment. Recent studies have shown that the host immune system is capable of responding to preneoplastic cells. Improved understanding of this response may provide novel opportunities for early detection and immune prevention of cancer.