Piper is one of the largest genera of flowering plants. The uniformity of its small flowers and the vast number of species in the genus has hindered the development of a stable infrageneric classification. We sampled 575 accessions corresponding to 332 species of Piper for the ITS region and 181 accessions for the psbJ-petA chloroplast intron to further test previous hypotheses about the major clades within Piper. Phylogenetic analyses were performed for each marker separately and in combination. The ITS region alone resolves eleven major clades within Piper, whereas the psbJ-petA intron fails to recover four of these major groupings and provides no resolution at the base of the phylogeny. The combined analysis provides support for ten monophyletic groups and offers the best hypothesis for relationships in Piper. Our massive ITS dataset allows us to assign confidently a large number of species in this giant genus to a major clade. Piper is here divided into ten major clades for which we provide a morphological description. Various clades and subclades are newly identified here: Peltobryon, Schilleria, Isophyllon, P. cinereum/P. sanctum. The clades described here provide a solid framework for future, and more focused, evolutionary studies. New names and combinations proposed herein include Piper bullulatum, P. hooglandii, and P. melchior.