Rapamycin is a curious drug. On the one hand it extends life and health span of genetically heterogeneous (wild type, healthy) mice when started in mid or late life; and in a dose responsive manner. Given over a lifetime, it also extends the life span of cancer prone mouse models and has positive effects in other models of age-caused diseases. On the other hand, it is routinely used long-term in (less healthy) transplant patients as an immunosuppressant to prevent allograft rejection, while a modified form (rapalog) improves immunity in the elderly. Another rapalog is effective in the long-term stabilization of disease in cancer patients. These seemingly incongruous thoughts—a drug that is supposed to suppress a major disease-defense system (including cancer) somehow extends life and health span in the lab and in cancer patients—has resulted in a certain level of cognitive dissonance regarding this drug. A black box warning that sirolimus (rapamycin) can increase the risk for cancer hasn’t helped to clarify things. What’s going on? Clearly a lot we do not understand. What is all this telling us about the systems (cell autonomous and non-autonomous) with which this drug interacts? I review progress toward the goal of clarifying the biology of this drug, and how all this fits into the general picture of preventing age-associated diseases to extend longevity; or the other way around, delaying aging to prevent age-caused maladies.