The technique of positional cloning has become a familiar component of modern human genetics research. After a halting start in the mid-1980s, the number of disease genes succumbing to cloning efforts based solely on pinpointing their position in the genome is growing exponentially. More than 40 genes have been identified so far. But the positional candidate approach, which combines knowledge of map position with the increasingly dense human transcript map, greatly expedites the search process and will soon become the predominant method of disease gene discovery. The challenge ahead is to apply such methods to identifying genes involved in complex polygenic disorders.