Using drugs to prevent cancer has long been sought, as many clues from the laboratory and observational population studies have pointed to several clues and candidate drugs. Testing these in the clinic requires huge numbers of subjects (well over 10,000) that have to be randomized to placebo or the active drug and then followed for many years, an expense that few companies or the government will take on. The first prevention drug, tamoxifen was approved in 1998 to lower the risk of getting breast cancer (lowered the rate from about 2% to 1% over 5 years). However, this drug is rarely used, in part because of bothersome side effects, but also more serious ones like an elevated risk of uterine cancer and blood clots. A cousin of tamoxifen, raloxifene (Evista), with a lower risk of both these side effects was approved in 2007. This class of drugs, known as selective estrogen receptor modulators (SERMs), also improves bone mineral density--Evista is actually approved for osteoporosis. Since the estrogen receptor pathway mediates many different physiological processes ranging from breast cancer to clotting to bone density, SERMs have been engineered, through slight chemical alterations in their structures, to be the perfect women's health drug--with the potential to lower cancer risk and to improve bone and cardiac health. Evista was designed to not produce stimulation of uterine cells as to avoid a known complication of tamoxifen--an increased risk of uterine cancer. While it did achieve that goal, its breast cancer risk-attenuating activity is not as good as tamoxifen's, and it still raises the risk of blood clots. Another SERM called lasofoxifene has come a little closer, with a recent update of a large randomized trial now showing a lowering of breast cancer rates by nearly 80%--that is from 1 in every 114 women to 1 in every 550 women over 5 years. It also lowered the bone fracture rate and even the stroke rate without increasing endometrial cancer risk. However, it did increase blood clotting--the one SERM side effect that we cannot seem to "engineer out." Still, the FDA earlier rejected lasofoxifene as a preventive drug because the overall death rate (from non-cancer causes) was higher in the low-dose arm compared to placebo even though it was not in the high-dose arm. This turn of events reflects the frustration by all parties--doctors, patients, researchers and the FDA itself. We have prevention drugs that can lower cancer risk with side effects that are much lower in number than the cancers prevented. So far, no drug is free of rare but serious side effects--and coupled with the less dangerous but still bothersome side effects, such as hot flashes and a myriad of less characterized symptoms, it is understandable why only a fraction of eligible patients opt for FDA-approved breast cancer prevention drugs. Also, there is no statistical difference in the overall death rate in prevention studies, in part because they were not designed to be large enough to detect them, but it may also be that we are preventing the less dangerous estrogen receptor-positive breast cancers.The field of cancer prevention is still very active but could use a shot in the arm. While the science behind it is very elegant, it appears that, like many other things in life, it comes down to a popularity contest. Doctors and patients will vote with their feet--with prescribing and compliance hinging on both a better side effect profile, and a bigger impact on saving lives, not just lowering the number of cancer cases.