Although Rap GTPases of the Ras family remained enigmatic for years, extensive studies in this decade have revealed diverse functions of Rap in the control of cell proliferation, differentiation, survival, adhesion, and movement. With the use of genetic engineering strategies, we have uncovered essential roles of Rap signaling in normal lymphohematopoietic cell development as well as its crucial involvement in the development of a wide spectrum of leukemia in manners highly dependent on the contexts of cell lineages. Incidentally, recent results also indicate an important role of Spa-1, a Rap GTPase-activating protein, in invasion and metastasis in human cancers. While it is unlikely that Rap can function as a classic oncogene by itself, like Ras, emerging findings unveil crucial involvements of Rap GTPases in the distinct aspects of malignancy, including leukemia genesis and cancer metastasis.