Heme oxygenase-1 (HO-1) and carbon monoxide (CO) modulate inflammation, proliferation/cell cycle and survival in a host of pathophysiological situations by reestablishing homeostasis. While several target genes and signaling pathways have now been elucidated that participate in HO-1/CO mediated protection, the events that occur in response to HO-1/CO under cellular stressors remain poorly understood particularly as they relate to therapeutic effects. Clearly there are differences among cell and tissue types driven by variations in basal gene expression profiles and more importantly under different activation states. In these instances where HO-1/CO mediate cytoprotection and restore homeostasis, critical regulatory and signaling mechanisms are in place to efficiently direct the cellular response. We propose that the HO-1 system acts as a biosensor for the cell. A fascinating aspect of the pleiotropic effects of the HO-1 system and the metabolic products involves the concept that its functional response befits the circumstances in which it finds itself whether prophylactically or therapeutically so as to ensure continued survival. This aspect of HO-1 and specifically the cellular response to CO as it relates to cell cycle and proliferation will be discussed in detail in this perspective.