The bone marrow (BM) is a multifactorial, highly dynamic, still not fully “mapped,” reservoir. The BM labyrinthine landscape is subject to a relentless debate on the specialized and stem/progenitor cells’ scattering within designated microareas. Certainly, BM tissue plays a watchdog role in bone modeling and remodeling, hematopoiesis, immune surveillance, and endocrine response integration. Parameters like tissue topographical distinctiveness, stiffness and porosity grade, and cells’ behavioral idiosyncrasies in terms of stem/progenitor cell housing, activation, and motility represent a knotty problem not easily solved. Given that the disruption of BM microdomains has been associated with a number of severe pathological disorders, the comprehension and preservation of the BM workspace at multiple levels have become mandatory. Solid evidence has showed the existence of an intricate and tightly regulated cross-talk between the BM cellular occupants. Direct physical cell-cell connections and soluble mediators, including cytokines, chemokines, growth factors, exosomes and microvesicles, orchestrate composite intracellular signaling routes. The spatiotemporal action of definite biofactors ensures a functional blood-producing organ with a physiological bone turnover and prompts the action of multipotent stromal/hematopoietic cells. Recently, significant research efforts have been addressed to build bioengineered niche-mimic models based on biofunctionalized scaffolds and organoid-like constructs. These artificial BM niches combine and transduce various aspects of bioinformatics and tissue engineering to unravel the complexities of BM organization. This chapter aims to unfold the recent breakthroughs in the understanding of a BM intramural cell-cell dialogue in a physiological and, in some cases, within an inflammatory background. BM maze is gradually being discovered, but there is still a long way to go.