Building on our ongoing efforts towards identifying candidate genes conditioning Southern root-knot nematode (RKN) resistance in upland cotton, we are working on a draft manuscript with an extensive characterization of interactions between G. hirsutum and M. incognita through differential gene expression and comparative transcriptomics using RNA-seq analyses of a nematode resistant (incompatible interactions) and susceptible (compatible interactions) lines at five different stages of nematode development inside RKN infested roots. Our results show that basal defense responses are activated both during compatible and incompatible interactions; albeit the responses are more pronounced in RKN resistant genotype compared to the susceptible line. In summary, nematode responsive genes related to defense pathways are often repressed during compatible interactions, while earlier induction, greater diversity, and higher degree of up-regulation of those genes are archetypal of incompatible interactions. A wide spectrum of disease resistance and putative resistance genes, pathogenesis-related genes, and genes corresponding to ligands and receptors are differentially expressed in response to nematode parasitism in G. hirsutum. These genes are mapped across the cotton genome and include candidate genes Gh_A11G3090 (PUB21) and Gh_A11G2836 (RPPL1), and Gh_D02G0259 (RLP12) in the QTL regions of chromosomes 11 and 14, respectively.