Fetal cell microchimerism is defined as the persistence of fetal cells in the mother after birth without any apparent rejection. Fetal microchimeric cells (FMCs) engraft into the maternal bone marrow for decades after delivery and are able to migrate to blood and tissues. This phenomenon was hypothesized to have a detrimental role in autoimmune diseases, but data are still controversial and debated. In malignant tumors, fetal cell microchimerism has been postulated to have a positive effect on tumor burden, although some evidence suggests that FMCs may be involved in neoplastic progression. At the peripheral level, circulating FMCs are less frequently detected in patients with thyroid cancer, breast cancer or other solid, hematologic malignancies than in healthy individuals, which suggests a protective role for fetal cell microchimerism. In tissues, FMCs have been found in tumor sections from malignancies such as thyroid, breast, cervix, lung cancers and melanomas and have been shown to differentiate into epithelial, hematopoietic, endothelial and mesenchymal cells. FMCs with hematopoietic differentiation have been postulated to have a role in destroying the tumor, whereas mesenchymal and epithelial cells could participate in repair processes. Endothelial cells, on the other hand, are believed to play a part in tumor progression. This Review provides an overview of the role of fetal cell microchimerism in autoimmune and benign or malignant nonautoimmune diseases. Moreover, the mechanisms by which fetal cell microchimerism is believed to modulate the protection against cancer or tumor progression will be discussed, together with future research directions.