Native African cereals (sorghum, millets) ensure food security to millions of low-income people from low fertility and drought-prone regions of Africa and Asia. In spite of their agronomical importance, the genetic bases of their adaptations to natural and anthropogenic selective pressures are still not well understood. Here we focus on Sorghum bicolor, which is the fifth cereal worldwide for grain production and constitutes the staple food for around 500 million people. The release of the genome sequence, its phylogenetic proximity with other important C4 species (maize, switchgrass, sugarcane) and its low genome complexity contribute to the interest on S. bicolor on a more fundamental level. We leverage transcriptomic and genomic resources to address the adaptive consequences of the domestication process. Despite gene flow with the wild pool, a clear domestication syndrome is visible in cultivated sorghum (plant architecture, shattering, dormancy and seed weight). Gene expression and nucleotide variability were analyzed in 11 cultivated and 9 wild accessions. The cultivated compartment harbors 30% lower genetic diversity than the wild pool, which supports the occurrence of a genetic bottleneck in the domestication history of sorghum. Furthermore, the crop gene pool showed polymorphism patterns in coding regions indicative of lower efficacy of purifying selection, suggesting that sorghum suffers from the cost of domestication. 949 genes are significantly differentially expressed between the two compartments. Among them, genes involved in internode elongation and cytoskeleton organization are over-expressed, while genes linked to photosynthesis and reduction-oxidation processing of seed storage proteins are under-expressed in the cultivated accessions. Further analyses revealed that domestication reduced significantly the variability of the isoform expression balance (expression ratio of the alternative proteins coded by a single gene) in cultivated sorghum. Overall