The understanding of the genetic architecture of a desirable trait is vital in enabling sustainable increased yields of a root crop such as cassava, especially in a low-input agricultural system. The understanding of desirable trait architecture is also vital for the sustained adoption of new cassava varieties by farmers and the market value of harvested roots. Given that cassava originated and was domesticated in Brazil, this study focused on characterizing landraces and modern breeding lines from a cassava germplasm bank in Brazil. The knowledge of the genomic landscape of these germplasms was then utilized to understand the impact of modern breeding practices on key trait architecture in African cassava programs. First, in collaboration with the Brazilian cassava program, I carried out a comprehensive genotyping of Brazilian cassava (Manihot esculenta Crantz) germplasm bank, with the aim of providing insights into diversification and domestication. Secondly, I addressed the potential toxic cyanide compound released upon cassava tissue disruption, causing neurological disorder upon monotonous consumptions of cassava roots without adequate detoxification. Lastly, I developed a population-based transcriptomics resource for studying developmental and physiological characteristics of cassava and also provided further insight on disease resistance. Key deliverables from these studies included: (1) Identification of a total of 1,536 individuals that represented the core diversity and 10 distinct genetic groups with heterogeneous linkage disequilibrium in the Brazilian germplasm bank. (2) Spatial population structure analysis revealed five ancestral populations related to distinct Brazilian ecoregions. (3) Estimation of historical relationships among identified populations suggested an early population split from Amazonian to Atlantic forest and Caatinga ecoregions, and active gene flows. (4) M. glaziovii introgression was identified and characterized and shown to be associated with past breeding efforts in Brazil. (5) Two major loci, encoding for an ATPase and a MATE protein, were identified in Brazilian germplasm that contributes up to 7 and 30% of the hydrogen cyanide (HCN) concentration in roots, respectively. (6) We validated HCN trait architecture consistency in African germplasm and diagnostic markers were developed for breeding applications. (7) Genomic characterization revealed: (i) the major role played by vacuolar transporters in regulating HCN content; (ii) the co‐domestication of sweet and bitter cassava targeted divergent HCN alleles in different geographical zones; and (iii) the major allele for high HCN in M. esculenta Crantz likely derives from its ancestor, M. esculenta subsp. flabellifolia. (8) Differential expression and weighted gene co-expression network analysis were performed to detect 8,820 significantly differentially expressed genes (DEGs), revealing similarity in expression patterns between tissue types and the clustering of detected DEGs into 18 gene modules. (9) Differential expression and pathway analysis targeting cassava mosaic disease identified 27 genes observed in plant-pathogen interaction pathways, and two peroxidase family proteins different from the CMD2 gene. (10) Finally, we provided population-based transcriptomics resources available to the research community in a web-based queryable cassava expression atlas.