Since its discovery, the E2F family of transcription factors has both fascinated and confused researchers. What started as a simple model of positive regulation of genes required for DNA synthesis by E2F has markedly expanded. E2F now appears to play contrasting roles in transcriptional activation and repression, proliferation and apoptosis, tumor suppression and oncogenesis, and possibly differentiation and DNA repair. How can we reconcile the apparently opposing functions of E2F in different contexts? Often adding to the confusion are the contrasting results obtained using distinct methods to study E2F and the difficulty of extrapolating mechanism from an observed endpoint. This review will attempt to address these issues. We will focus on biological functions of E2F elucidated via genetic studies that are expanding our understanding of how E2F family members are integrated into pathways controlling proliferation, apoptosis, development and tumorigenesis. We will examine several alternative genetic approaches to understanding E2F activities, including overexpression studies in cell culture, the analysis of E2F function in flies and worms, and most extensively, the use of E2F-gene-disrupted mice to determine physiological roles for E2F proteins. Some of the questions that we will address are: