Osteopetrosis is a disease of bone resorption that may be inherited with m a n y separate genes in various m a m m a l i a n species (1, 2). There are four distinct mutations in the mouse that can individually result in this disorder: osteopetrotic (op) (3), microopthalmic (mi) (4), gray-lethal (gl) (5), and osteosclerotic (oc) (6). A major advance in our understanding of osteopetrosis was provided by the experiments of Walker (7-9), demonstrating the ability of normal hemopoietic cells to cure this disorder in mi/mi and gl/gl mice. Additionally, it was shown that spleen cells from these mutants transfer the disease into irradiated normal littermate recipients (8, 9). The response of other murine osteopetrotic m u t a n t s in transplantation assays remains unknown. At the cellular level, osteopetrosis is a disease of a functionally a n d / o r quantitatively a b n o r m a l osteoclast (1, 10), The osteoclast is a multinuclear cell that is most p r o b a b l y formed through a fusion of cells of the m o n o c y t e -m a c r o p h a g e lineage (11). Therefore, the osteoclast belongs to the progeny of the hemopoietic stem cell (HSC) 1 (12, 13), and this explains the positive response of mi/mi and gl/gl mice to transplants of hemopoietic cells. This cure of osteopetrosis by hemopoietic grafts is a more general p h e n o m e n o n and was recently observed also in juvenile osteopetrosis in man (14, 15) and in two rat mutants: ia/ia (16) and op/op (17). Studies (18) in op rat additionally linked osteopetrosis with abnormalities in the T lymphocyte system. O n the other hand, the osteopetrosis in tl/tl rat failed to respond to the bone marrow transplant (19), suggesting that the p r i m a r y lesion in this m u t a n t resides beside the hemopoietic tissue, presumably in the hemopoietic microenvironment (HM). The H M is m a d e by stromal tissue of bones and spleen, histogenetically different from the hemopoietic system and largely derived from cells with fibroblast-like morphology (20). The classic example of the disorder of H M is a n e m i a in S1/S1 d mice, which is * Supported in part by a grant from the Polish Academy of Sciences to W. Wiktor-Jedrzeiczak , and by the Naval Medical Research and Development Command. The opinions and assertions contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the U. S. Navy Department or the naval service at large. The experiments reported herein were conducted according to the principles set forth in the current edition of the "Guide for the Care and Use