The model pathogen Ralstonia solanacearum GMI1000 is the causal agent of the bacterial wilt disease that attacks many solanaceous plants and other hosts but not tobacco (Nicotiana spp.). We found that two type III secretion system effector genes, avrA and popP1, are limiting the host range of strain GMI1000 on at least three tobacco species (N. tabacum, N. benthamiana, and N. glutinosa). Both effectors elicit the hypersensitive response (HR) on these tobacco species, although in different manners; AvrA is the major determinant recognized by N. tabacum and N. benthamiana, while PopP1 appears to be the major HR elicitor on N. glutinosa. Only the double inactivation of the avrA and popP1 genes allowed GMI1000 to wilt tobacco plants, thus showing that GMI1000 intrinsically possesses the functions necessary to wilt tobacco plants. A focused analysis on AvrA revealed that the first 58 N-terminal amino acids are sufficient to direct its injection into plant cells. We identified a hypervariable region in avrA, which contains variable numbers of tandem repeats (VNTR), each composed of 12 base pairs. We show that an 18–amino acid region in which the VNTR insertion occurs is an important domain involved in HR elicitation on N. benthamiana. avrA appears to be the target of various DNA insertions or mobile elements that probably allow R. solanacearum to evade the recognition and defense responses of tobacco.