Fungal endophytes are receiving increasing attention by natural product chemists due to their diverse and structurally unprecedented compounds which make them interesting candidates for drug discovery. One fungal genus which is especially productive with regard to the accumulation of a diverse array of mostly bioactive compounds is Pestalotiopsis. This review demonstrates the unique chemical diversity of taxa from this genus and describes their reported bioactivities. To date, alkaloids, terpenoids, isocoumarin derivatives, coumarins, chromones, quinones, semiquinones, peptides, xanthones, xanthone derivatives, phenols, phenolic acids, and lactones, have been reported from Pestalotiopsis species, making this genus a particularly rich source for bioprospecting when compared with other fungal genera. More than 130 different compounds that have been isolated from various species of Pestalotiopsis are covered in this review and their structures are reported within a biogenetic context. Bioassays disclosed that antifungal, antimicrobial, and antitumor activities are the most notable bioactivities of secondary metabolites isolated from this genus. Possible biogenetic pathways for monoterpenes, sesquiterpenes, quinones, and lactones that are covered in this review article are also illustrated.