Diabetes and cardiometabolic disorders such as hypertension and obesity are major risk factors for the development of cardiovascular disease, with a wealth of evidence suggesting that oxidative stress is linked to the initiation and pathogenesis of these disease processes. With yearly increases in the global incidence of cardiovascular diseases (CVD) and diabetes, numerous studies have focused on characterizing whether upregulating antioxidant defenses through exogenous antioxidants (e.g. vitamin E, vitamin C) or activation of endogenous defenses (e.g. the Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense pathway) may be of benefit. The dietary isothiocyanate sulforaphane (SFN) is currently the subject of several clinical trials for a variety of disease states, including the evaluation of its therapeutic potential to ameliorate diabetic and cardiometabolic complications. SFN is a well characterized and potent Nrf2 inducer, however recent studies suggest its protective actions may be in part mediated by its modulation of various pro-inflammatory (e.g. Nuclear factor-kappa B (NFκB)) and metabolic (e.g. Peroxisome Proliferator-Activator Receptor Gamma (PPARγ)) signaling pathways. The focus of this review is to provide a detailed analysis of the known mechanisms by which SFN modulates Nrf2, NFκB and PPARγ signaling and crosstalk and to provide a critical evaluation of the evidence linking these transcriptional pathways with diabetic and cardiometabolic complications and SFN mediated cytoprotection. To allow comparison between rodent and human studies, we discuss the published bioavailability of SFN metabolites achieved in rodents and man in the context of Nrf2, NFκB and PPARγ signaling. Furthermore, we provide an update on the functional outcomes and implicated signaling pathways reported in recent clinical trials with SFN in Type 2 diabetic patients.