MicroRNA-155 (miR-155) is a key regulator of immune cell development and function. This study identifies SHIP1 as a direct target of miR-155, showing that miR-155 represses SHIP1 through direct 3'UTR interactions, which are highly conserved. Overexpression of miR-155 in hematopoietic cells leads to reduced SHIP1 levels, increasing Akt activation in response to LPS. Physiological regulation of miR-155 also represses SHIP1 in macrophages. Knockdown of SHIP1 in the hematopoietic system using a miR-155-formatted siRNA results in a myeloproliferative disorder similar to that observed in miR-155-expressing mice. These findings establish a molecular link between miR-155 and SHIP1, highlighting the importance of SHIP1 repression in miR-155 biology. SHIP1 is a negative regulator of Akt, and its repression by miR-155 contributes to increased myeloid cell proliferation and altered immune responses. The study also shows that miR-155 expression and SHIP1 knockdown lead to similar pathological outcomes, including splenomegaly and extramedullary hematopoiesis. These results suggest that miR-155 represses SHIP1 to regulate hematopoiesis and immune function, with implications for diseases such as cancer and autoimmunity. The study underscores the role of miR-155 in modulating SHIP1 expression and highlights the potential therapeutic relevance of targeting this interaction.MicroRNA-155 (miR-155) is a key regulator of immune cell development and function. This study identifies SHIP1 as a direct target of miR-155, showing that miR-155 represses SHIP1 through direct 3'UTR interactions, which are highly conserved. Overexpression of miR-155 in hematopoietic cells leads to reduced SHIP1 levels, increasing Akt activation in response to LPS. Physiological regulation of miR-155 also represses SHIP1 in macrophages. Knockdown of SHIP1 in the hematopoietic system using a miR-155-formatted siRNA results in a myeloproliferative disorder similar to that observed in miR-155-expressing mice. These findings establish a molecular link between miR-155 and SHIP1, highlighting the importance of SHIP1 repression in miR-155 biology. SHIP1 is a negative regulator of Akt, and its repression by miR-155 contributes to increased myeloid cell proliferation and altered immune responses. The study also shows that miR-155 expression and SHIP1 knockdown lead to similar pathological outcomes, including splenomegaly and extramedullary hematopoiesis. These results suggest that miR-155 represses SHIP1 to regulate hematopoiesis and immune function, with implications for diseases such as cancer and autoimmunity. The study underscores the role of miR-155 in modulating SHIP1 expression and highlights the potential therapeutic relevance of targeting this interaction.