Much progress has been achieved in the last decade in terms of development of laboratory techniques, reagents and in vivo models. They have undoubtedly contributed to better and more accurate investigations. Despite a concerted effort by many investigators, however, breakthroughs have been minimal. The development of adequate in vitro and in vivo techniques for drug screening, and the intensified and systematic screening, has so far not resulted in the discovery of an effective therapy. The reason for the failure may well be due to the unique biological niche the parasite occupies (discussed at length in the first chapter in this volume). Its location beneath the cell membrane, but outside the cell cytoplasm, may prove a crucial element that needs to be considered when designing new therapeutic approaches. Laboratory investigations on two drugs currently used against chronic Cryptosporidium parvum in acquired immune deficiency syndrome (AIDS) are discussed. This chapter also provides information and the rationale for work in progress in our laboratory that relates to the development of novel approaches for control of the disease. This includes the identification of molecular targets of parasite origin for drug design, and studies on the structure-activity relationships of partially effective drugs with a view to synthesize more effective derivatives. Other investigations attempt to establish the role of secretory antibody, and the merit of repeated mucosal immunizations as a means of providing protection to individuals with AIDS who are at risk of developing chronic C. parvum infection.