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The established paradigm of stress axis is not only borne by the hypothalamic-pituitary-adrenal (HPA) axis. There are various “fine-tuners” in the form of neuromodulators whose intricate functioning is under active investigation. Two such neuromodulators, namely nociceptin and orexin are interesting candidates to further evaluate their respective roles and possible cross-talk in due course of stress. In addition, apart from this outlook toward stress, immune stress is also perceived as an impending threat to the physiology and probably implicates the HPA axis in ways that we fail to comprehend with our current crux of knowledge. Sepsis or system inflammatory response syndrome is an exemplary of such an immune stress where the role of the HPA axis has been evidentially supported. An interesting question which arises is how would neurologically perceived stress and sepsis be guided by various neuromodulators. The scope of this review is to evaluate the existing literature where we look at the role of nociceptin and orexin in guiding the complex etiology of stress and sepsis, respectively. Extensive review has suggested, there also might be a hypothetical “cross-talk” between nociceptin and orexin, though this again has to be supported by further investigations.