The axis between lipid oxidation products and cell death is explicitly linked. 4-Hydroxynonenal (HNE), as well as other lipid oxidation products was also established to induce apoptosis in various experimental settings. Yet, the decision leading to apoptotic execution not only includes upregulation of pro-apoptotic signals but also involves a downregulation of anti-apoptotic signals. Within the frames of this paradigm, HNE acts significantly different from other lipid oxidation products in the regulation of two widely known anti-apoptotic elements, Nuclear Factor-κB (NF-κB) transcription factors and its target anti-apoptotic B-Cell Lymphoma-2 (Bcl-2) protein. Even so, a review inclusively linking these anti-apoptotic factors and their crosstalk upon HNE exposure is still at demand. In order to elucidate presence of such crosstalk, reports on the link between HNE and NF-κB pathway, on the link between HNE and anti-apoptotic Bcl-2 and on the crossroad of these links during HNE exposure were summarized and discussed. IKK, the upstream kinase of NF-κB, has been shown to regulate HNE mediated phosphorylation and inactivation of Bcl-2 by our group. Based on this observation and other studies reporting on HNE-NF-κB pathway interaction, IKK was proposed to mediate the crosstalk of NF-κB pathway and anti-apoptotic Bcl-2 protein, when HNE is present. These reports further suggested that HNE based inhibition of NF-κB pathway is highly likely. Besides, evidence on the HNE-anti-apoptotic Bcl-2 axis supported the deduction of HNE mediated NF-κB pathway inhibition and IKK mediated Bcl-2 inactivation. In conclusion, through combining all evidences, three possible scenarios intervening the HNE mediated crosstalk between NF-κB pathway and anti-apoptotic Bcl-2 protein, was extrapolated.