For several decades, advances have been made in venom characterization, mechanism of toxicity, and antivenom therapy. Much of this research has been based on models of the blood vascular system, to analyze the pharmacokinetics of venoms and antivenoms. However, in clinical envenomations, venom is injected into the interstitial space and an absorption process is necessary before it reaches the bloodstream. Absorption may occur by way of the blood or lymphatic capillaries, depending on the physicochemical properties of the molecules involved. Until recently, the role of the lymphatics in envenomation remained essentially unexplored, although several reports have demonstrated the fundamental role of the lymphatic system in the absorption of therapeutic proteins, administered subcutaneously. This review describes the absorption process, from the interstitial space and extracellular matrix through the entry into the blood capillaries and early lymphatics. Venom toxins interact with hyaluronic acid in the extracellular matrix, facilitating interstitial spread before entry into the vessels, and they induce local damage to the vascular endothelium, resulting in local hemorrhage and edema and altering the absorption characteristics of damaged vessels. Large molecules are absorbed primarily via the lymphatics, providing them a fundamentally different toxicokinetic profile from that of smaller toxins for which direct access to the blood capillaries is possible. Improved knowledge of the mechanism and factors influencing the subcutaneous venom absorption can improve the understanding of the role of edema, patterns of local injury, the toxicokinetics of envenomation, the effect of pressure immobilization, the pharmacodynamics and dosing of antivenom, and the phenomenon of recurrent venom effect.