During the past decade, novel revolutionary frontiers have been opened at the immuno-inflammatory research fields. Indeed, with the help of modern, state-of-the-art technologies (immunomics and other omics, systems biology) it was identified that the immune system is much more complex than previously thought and that its proper functions are defined by multi-directional intercellular communications between cellular (and humoral) components of innate and adaptive immunity. Furthermore, it was also unambiguously shown that the homeostatic regulation of the immune-inflammatory responses is fundamentally dependent on constant communication with the highly versatile (and also very complex) microbiota inhabiting the barrier surfaces of the human body. Of further importance, extensive research efforts of the past decade have also revealed that altered immunological and (chronic) inflammation-related regulations play key roles in the pathogenesis of multiple cardiovascular (e.g. atherosclerosis) and metabolic (e.g. obesity) diseases, as well as, in cancer initiation, development, and progression. No wonder, therefore that immuno-inflammatory (either ‘classical’ or related) diseases are now considered as the most prevalent human pathologies. The complexity of the immune system requires novel therapeutic strategies to manage the immuno-inflammatory conditions. Most importantly, novel, combined and personalized pharmacological, biological, and (possibly) gene therapeutic efforts are suggested. However, we are convinced that these combined therapeutic protocols could only be successful if future research activities systematically and mechanistically uncover the (often redundant) genetic, transcriptomic, molecular, cellular and intercellular immune signaling pathways. Moreover, define those functional patterns whose genetic or acquired alterations could lead to the manifestation of the given pathological condition.