Normal DNA replication is stringently regulated to ensure a timely occurrence no more than once per cell cycle. Abrogation of the exquisite control mechanisms that maintain this process results in detrimental gains and losses of genomic DNA commonly seen in cancer and developmental defects. Replication initiation proteins, known as prereplicative complex (pre-RC) proteins, serve as a primary level of regulation, controlling when DNA replication can begin. Unsurprisingly, several pre-RC proteins are overexpressed in cancer and serve as good tumor markers. However, their direct correlation with increasing tumor grade and poor prognosis has posed a long-standing question: Are pre-RC proteins oncogenic? Recently, a growing body of data indicates that deregulation of individual pre-RC proteins, either by overexpression or functional deficiency in several organismal models, results in significant and consistently perturbed cell cycle regulation, genomic instability, and, potentially, tumorigenesis. In this review, we examine this broad range of evidence suggesting that pre-RC proteins play roles during oncogenesis that are more than simply indicative of proliferation, supporting the notion that pre-RC proteins may potentially have significant diagnostic and therapeutic value.