Pharmacologic or nutritional prevention of lung cancers is needed, especially for 60 million Americans who are former smokers. A portfolio of large-scale trials of beta-carotene, beta-carotene with and without vitamin E, and beta-carotene plus vitamin A demonstrated no benefit whatsoever from beta-carotene. The α-Tocopherol/β-Carotene Trial and the β-Carotene and Retinol Efficacy Trial found significant increases in lung cancer risk and total mortality. Laboratory research soon identified multiple adverse molecular effects. Nevertheless, chemoprevention remains an active, promising strategy, with new hypotheses and new candidate agents, including many already approved as therapies. The most active area currently is focused on selective inhibition of arachidonic metabolism, both Cox-2 and Lox pathways.