Studies were carried out with clonal PC12 rat pheochromocytoma cells to test and elaborate the "priming" model for the mechanism by which nerve growth factor (NGF) promotes neurite outgrowth. The rate of appearance, initial extent of elongation, and insensitivity to inhibitors of transcription for neurites regenerated by passaged PC12 cells were all found to increase progressively as a function of time of NGF pretreatment. Cells pretreated (or "primed") with NGF were thus able to rapidly regenerate long processes even when RNA synthesis was blocked. The long-term, progressive nature of neurite outgrowth and priming were not entirely accounted for by cell cycle effects. These observations were thus consistent with a mechanism in which NGF promotes process outgrowth by specifically stimulating cells to synthesize and progressively accumulate substances which are required for neurite production and elongation. This process appeared to require RNA transcription and the accumulation of specific rather than total cell constituents. Priming occurred for cells grown in suspension or in the presence of inhibitors of microtubule assembly. Priming and neurite outgrowth were suppressed at high cell density and were not elicited by exposure to depolarizing agents. Examination of the properties of NGF-promoted neurite outgrowth by cultured neurons suggests that priming may occur during development of the normal nervous system. It is also conceivable that self-priming may be a feature of growth factors in addition to NGF.