The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a double-blind, randomized, active-controlled hypertension treatment trial. ALLHAT was designed to compare the effects of antihypertensive treatment with a calcium channel blocker, an ACE-inhibitor, or an α-receptor blocker, each compared to a thiazide-type diuretic, in reducing the risk of coronary heart disease and other cardiovascular outcomes. Active follow-up of 42,418 participants ended on March 31, 2002 (February 15, 2000 for doxazosin participants), with an average follow-up of 4.9 years (3.2 years for doxazosin). In addition to the expected challenges of conducting a major clinical trial, several unexpected challenges arose during the course of ALLHAT, including several interesting clinical trials and statistical issues. This presentation will highlight some of these.