When highly purified nuclei of Swiss mouse 3T3 cells are incubated with gamma-32P-ATP, radioactivity is incorporated into phosphatidic acid and the two polyphosphoinositol lipids, phosphatidylinositol(4)P and (4,5)P2. If the cells are pre-treated with IGF-I, the incorporation into the polyphosphoinositides is decreased. This effect is maximal by 2 min, is transient in that it disappeared by 1 hr, and is increased markedly by the co-addition of bombesin, even though bombesin alone has no effect. Friend cells exhibit a related phenomenon in that the labelling of PIP2 in isolated nuclei is increased by conditions which cause erythroid differentiation (DMSO addition). We suggest that some aspect of nuclear polyphosphoinositide metabolism is modified when the nucleus is induced to divide or to differentiate, and that this change in inositide metabolism is a very early event in the sequence leading to cell division or differentiation.