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Research into the biology of endotoxin (aka lipopolysaccharide; LPS) began well over 100 years ago and has had many unexpected turns. The phenomenon of endotoxin tolerance was among these and has engendered immense curiosity over the years. Sly and colleagues (this issue of Immunity) have taken an important step toward understanding the phenomenon of endotoxin tolerance and have enhanced our comprehension of LPS signaling as a whole by demonstrating that the cytosolic phosphatase SHIP is required to permit the development of an LPS-refractory state in macrophages and mice.