Lymphatics of the dog were perfused between the hind leg and the left thoracic duct outlet with chemicals of various molecular weights. Almost three-fourths of the albumin (molecular weight 68,000) which was infused was recovered in the lymph. Approximately half of the infused inulin (molecular weight 5,000) was recovered in the lymph. Only small amounts of lower molecular weight substances (creatinine, thiotepa, 5-fluorouracil) could be recovered. The study supports the concept that the permeability of the lymphatics depends to an appreciable extent on molecular weight. In a second group of 10 dogs both thoracic ducts were ligated for 1 to 4 weeks, after which the left thoracic duct was cannulated and the albumin infusion performed. In this group more than half of the albumin appeared in the plasma of 6 of the dogs, indicating the probable development of major lymphatico-venous shunts. A similar result was obtained in one human. The studies suggest that any substance with a therapeutic usefulness dependent upon its remaining within the lymphatic vessels can only be used in an unobstructed lymphatic system and must be of a large molecular weight. Conversely, it is unlikely that measurement of the content of any small molecular weight substance in the lymph can be interpreted as indicative of the content of lymph in any other part of the body.