Oncogene-induced senescence is a mechanism of tumor suppression that restricts the progression of benign tumors. Important advances have been made toward elucidating the mechanisms that regulate this response; however, there is presently no unified model that integrates all current findings. DNA damage, replicative stress, reactive oxygen species, heterochromatin formation and negative feedback signaling networks have all been proposed to play an integral role in promoting senescence in response to various oncogenic insults. In all cases, these signals have been shown to function through Rb and p53, but utilize different intermediaries. Thus, it appears that senescence is not triggered by a single, linear series of events, but instead is regulated by a complex signaling network. Accordingly, multiple proteins may cooperate to establish a senescence response, but the limiting signal (s) may be dictated by the initiating genetic alteration and/or tissue type. This review will focus on integrating current models and will highlight data that provide new insight into the signals that function to suppress human tumor development.