The Spi-1/PU.1 protein is a transcriptional regulator of the Ets family. It is a key element in the development and the maturation of the granulocytic, monocytic and B lymphoïd lineages. Spi-1/PU.1 is involved neither in erythropoiesis nor in megacaryopoiesis. The transcriptional activation of Spi-1 during the erythroleukemic process induced by the Friend virus in mice is a primary event in the malignant transformation of the proerythroblast. The pathology developed by the Spi-1 transgenic mice revealed that overexpression of Spi-1/PU.1 in early erythroid cells blocks their differentiation. The function of Spi 1/PU.1 in normal hematopoiesis seems related to the ability of the protein to promote expression of various lymphoid and myeloid genes by binding responsive elements in the transcriptional promoters and enhancers. However the transcription factor Spi-1/PU.1 which binds DNA is also capable to bind RNA and to interfere with splicing process of pre-messenger RNAs. This dual function suggests new hypotheses about the function of Spi-1 in normal hematopoiesis as in erythroleukemia. This paper provides a general view of the data that enlight the major role of Spi-1 at once in normal lymphomyelopiesis and malignant erythropoiesis.