Ras proteins normally relay growth-promoting signals from many activated cell surface receptors, and they are altered by oncogenic point mutations in approximately 30% of human cancers. Activating KRAS and NRAS mutations are especially common in malignancies of the pancreas, lung, and colon, and in myeloid leukemia. Here, we discuss general strategies for targeting hyperactive Ras signaling in cancer cells with specific reference to myeloid malignancies.