Our emerging understanding of oxygen delivery to the tissues is that the blood flow within the smallest arterioles is tightly organized within repeating networks across the tissue. Central to this new paradigm are the concepts of vascular communication between the beginning and end of the network (via gap junctions), and its relation to flow sensing by the vascular endothelium (flow mediated dilation). In the normal resting state, flow distribution into successive branches along a central feed occurs with most flow (red blood cells, RBC) going to the first branch and successively less for sequential branch arterioles. This RBC distribution is linked to the total area of tissue fed by downstream capillaries, and ensures a uniform oxygen delivery. In inflammatory states, the flow distribution is significantly altered; RBC are shunted through the central feed with most flow going to the furthest most branch downstream. Oxygen delivery is not uniform. Further, both gap junctional activity and flow sensing are impaired. This occurs in a wide range of inflammatory states that includes: diabetes, obesity, pharmacologically induced inflammatory states, and inflammation that accompanies thermal wounds. Ongoing work targets the molecular basis for these abrupt and significant changes in flow distribution. The arterioles at this level are ~2 times the diameter of the RBC – hence they are large particles relative to the size of the tube in which they travel (the arteriole). The 3-D architecture of the arteriolar branch point affects how easily the RBC passes to that branch. Additionally, at this level the flow itself is viscous driven, with a low inertial component (Re <1). The independent impact of the flow properties and the particle:tube dimensions is studied in vitro in microchannels, where the relevant rheological factors can be scaled and controlled. Our work employs computational modeling of the fluid mechanics, the physiology of arteriolar network blood flow (in vivo and in vitro), and precise genomic manipulation of key proteins in healthy and vascular disease states.