Wild Manihot species are the source of traits for the genetic enhancement of cassava (Manihot esculenta; 2n = 2x = 36 chromosomes), the most important root crop of the developing world. Cassava originated by hybridization between two wild Manihot species followed by vegetative propagation of the selected hybrid(s) by early farmers. Many wild Manihot species are available in tropical America, though in recent decades some Manihot species are threatened by extinction, due to changes of environment and destruction of their natural habitats. It will be very important to preserve Manihot genetic resources in the northern Amazon, which seems to be the main location for domestication of cassava. Southern Goias and western Minas Gerais (Brazil) are the primary centers of diversity of Manihot species with about 38 of the 98 known wild species as diploids (2n = 36). In situ conservation of Manihot species in their microcenters of diversity such as Chapada de Veiadeiros, Corumba de Goias-Pirenopolis and Goias Velho in Central Brazil should be actively pursued to save this genetic endowment of cassava. Research of Manihot species in their natural habitats revealed their genetic endowment for traits providing tolerance to drought-prone environments, adaptation to cool temperatures or soil with aluminum toxicity. The ex situ conservation of 35 Manihot species at the University of Brasília provides a complementary approach that also allows the search for valuable traits among its holdings, e.g. 18 species were found to be interesting sources for further use in cassava breeding. Manihot species are providing a means for broadening the genetic base of cassava cultigens and for incorporating host plant resistance against major pathogens and pest affecting this crop, e.g. Cassava Mosaic Disease in Africa, or improving the nutrition quality of the roots, e.g. by enhancing pro-vitamin A and protein contents. Inter-specific crosses remains as the main breeding tool for such introgression of alleles from wild Manihot species into the cassava gene pool. Inter-specific hybrids between cassava and its wild relatives show relatively regular meiosis because barriers within the Manihot genus appear to be week due to recent evolution of the group. The occurrence of 2n gametes or the use of colchicine for chromosome doubling allows manipulating polyploidy for the genetic improvement of cassava. Both polyploidy and apomixis could contribute to speciation in the Manihot genus. Polyploidy offered genetic variability while apomixis was responsible for perpetuating new hybrids with enhanced adaptation to specific environments. The above approaches show the potential of conserving Manihot genetic resources through use in cassava breeding, particularly for improving its adaptation to the changing environments, where farmers grow the crop, and for providing more micronutrient dense food.