Given the inefficiency of current therapies for cancer, we have been exploring the approach of prophylactic immunization for the prevention of most or all types of cancer. Neoplastic cells express new antigens, many of which represent early embryonic antigens which may be expressed only in very early stages of normal gestation. Because the mammalian immune system learns to discriminate “self” from “non-self” very late in gestation, early embryonic gene products are potentially immunogenic. Therefore, we reasoned that immunization against embryonic stem cells (ESC), alone or in combination with murine fibroblasts (STO) expressing GM-CSF (STO-GM; combination immunization ESC/STO-GM) might prevent the growth of implantable tumors. This was tested in C57Bl/6 mice (initial body wt. ˜ 20 g) which were vaccinated 2× (10 days apart) with 2 × 105 ESC or ESC + 2 × 105 STO-GM. Ten days after the boost, the mice were challenged with 5 × 104 Lewis lung carcinoma s.c. Thirty days following challenge, 100% of control mice had developed tumors and had been sacrificed. In contrast, only 30% of ESC-vaccinated and 10% of ESC/STO-GM vaccinated animals developed tumors. The surviving animals were tumor free for ˜ 9 months (two independent experiments, 10 animals/group; p < .0001 by ANOVA). A similar immunization with ESC/STO-GM invoked a significant delay (˜ 2×) in the appearance of implanted B16 melanoma (10 animals/group; p < .01 by ANOVA). Further investigations revealed that animals vaccinated with ESC/STO-GM mounted a marked inflammatory response (as measured by the recruitment of macrophages and neutrophils) when challenged by i.p. injection of B16 cells. Both humoral and cell-mediated immunity may be involved in this anti-tumor effect. Splenocytes from vaccinated—but not control—mice exhibited a powerful tumor cell-specific cytolytic resonse against Lewis lung carcinoma, with substantial tumor cell killing at effector:target ratios as low as 2:1 and almost complete kill at 50:1. Furthermore, sera from immunized mice cross react with discrete antigens from several different tumors including Lewis lung carcinoma and B16 melanoma. In summary, vaccination of mice with live ESC protects against an implantable lung adenocarcinoma and, to a lesser extent, B16 melanoma. These results raise the prospect of the prophylactic vaccination of humans—especially those with hereditary predispositions to cancer—against a wide variety of neoplastic diseases.