Gossypium barbadense is widely cultivated because of its extra-long staple cotton with superior luster, silkiness and high yield. These economically important traits were selected during initial domestication of an agronomically inferior wild ancestor, followed by millennia of human-mediated selection. To reveal the effects of this history on the cotton fiber transcriptome, we conducted comparative expression profiling on mechanically isolated fiber cells at three different stages encompassing early, mid, and late fiber elongation in wild (K101) and domesticated (Pima S-7) accessions, using a microarray platform that interrogates 42,429 unigenes. The distribution of differentially expressed genes across developmental stages was different in the two accessions, with a shift toward greater change earlier in cultivated than in wild G. barbadense. Approximately 4200 genes were differentially expressed between wild and domesticated accessions at one or more of the stages studied. Domestication appears to have led to enhanced modulation of cellular redox levels and the avoidance or delay of stress-like processes. Prolonged fiber growth in cultivated relative to wild G. barbadense is associated with upregulation of signal transduction and hormone signaling genes and down-regulation of cell wall maturation genes. Clues are provided into the processes and genes that may unwittingly have been selected by humans during domestication and development of modern elite lines. Several of the transcriptomic differences between wild and domesticated G. barbadense described here appear to have parallels in a second domesticated cotton species, Gossypium hirsutum, suggesting that replicated domestication of two different species has resulted in overlapping, parallel, metabolic transformations.