One of the most striking features of mammalian chromosomes is the variation in G+C content that occurs over scales of hundreds of kilobases to megabases, the so-called 'isochore' structure of the human genome. This variation in base composition affects both coding and non-coding sequences and seems to reflect a fundamental level of genome organization. However, although we have known about isochores for over 25 years, we still have a poor understanding of why they exist. In this article, we review the current evidence for the three main hypotheses.