Desmoplakin (DP) is a key component of cellular adhesion junctions known as desmosomes; however, recent investigations have revealed a novel location for DP in junctions separate from desmosomes termed complexus adherens junctions. These junctions are found at contact sites between endothelial cells that line capillaries. Few studies have focused on the function of DP in de novo capillary formation (vasculogenesis) and branching (angiogenesis) during tumorigenesis, embryonic development, cardiovascular development or wound healing. Only recently have investigations begun to determine the effect the loss of DP has on capillaries during embryogenesis (i.e. in DP–/– mice). Evidence shows that the loss of desmoplakin in vivo results in leaky capillaries and/or capillary malformation. Consequently, the goal of this study was to determine the function of DP in complexus adherens junctions during capillary formation. To accomplish this goal, we used siRNA technology to knock down desmoplakin expression in endothelial cells before they were induced to form microvascular tubes on matrigel. DP siRNA treated cells sent out filopodia and came in close contact with each other when plated onto matrigel; however, in most cases they failed to form tubes as compared with control endothelial cells. Interestingly, after siRNA degradation, endothelial cells were then capable of forming microvascular tubes. In depth analyses into the function of DP in capillary formation were not previously possible because the tools and experimental approaches only recently have become available (i.e. siRNA). Consequently, fully understanding the role of desmoplakin in capillary formation may lead to a novel approach for inhibiting vasculo- and angiogenesis in tumor formation.