The molecular pathway leading to pituitary tumorigenesis is still largely unknown and is one of the challenges of the endocrine oncology. The development of pituitary adenomas in HMGA2 transgenic mice and the finding of HMGA2 amplification and overexpression in human pituitary adenomas led us to investigate the mechanism by which the HMGA2 gene plays a crucial role in pituitary oncogenesis. This mechanism has been recently described by our group: it entails the acetylation of E2F1, and its consequent enhanced activity, following the displacement of HDAC1 from the pRB/E2F1 inhibitory complex. Based on the mating between HMGA2 transgenic and E2F1 knockout mice, the activation of E2F1 appears to be the main mechanism of the onset of HMGA2-induced pituitary adenoma development. Nevertheless, other events may be also involved in this process, and are discussed here.