In comparative genomics, a transposition is an operation that exchanges two consecutive sequences of genes in a genome. The transposition distance between two genomes, that is, the minimum number of transpositions needed to transform a genome into another, is, according to numerous studies, a relevant evolutionary distance. The problem of computing this distance when genomes are represented by permutations is called the Sorting by Transpositions problem (SBT), and has been introduced by Bafna and Pevzner [3] in 1995. It has naturally been the focus of a number of studies, see for instance [17], but the computational complexity of this problem has remained undetermined for 15 years. In this paper, we answer this long-standing open question by proving that the Sorting by Transpositions problem is NP-hard. As a corollary of our result, we also prove that the following problem, rst described in [10], is NP-hard: given a permutation , is it possible to sort using exactly db( )=3 transpositions, where db( ) is the number of breakpoints of ?