For the past 170 years, there have been two main competing ideas about what causes cardiovascular disease. One of them, the cholesterol or lipid hypothesis, has come to dominate. The alternative hypothesis has had different names over the years — e.g., the encrustation hypothesis, thrombogenic hypothesis, and response to injury hypothesis. In the first article in this four-part series, Dr. Malcolm Kendrick explains this alternative hypothesis, outlines its brief history, and proposes why it may have fallen out of favor.