Bacterial wilt, also known as brown rot of potato, is an economically significant disease of solanaceous vegetables, which is caused by Ralstonia solanacearum. Defense against R. solanacearum is a challenging task requiring the combined application of different treatments in an integrated manner. By using molecular biologic techniques, new transgenic plant lines with improved pathogen resistance can be generated, while facilitating deeper knowledge of the molecular mechanisms involved in plant–pathogen interactions. We aimed to generate silencing and overexpressing constructs to obtain transformed S. tuberosum lines resistant to R. solanacearum. After an exhaustive literature search, we chose four genes with probable relations with R. solanacearum resistance in potato: [1] MKK1, which is part of the mitogen-activated protein kinase (MAPK) gene family, building up a phosphorelay cascade; [2] WAT1, a gene responsible for secondary cell wall deposition; [3] SK23, encoding a GSK3-/SHAGGY-like kinase, which has been earlier proven to be in negative correlation with pathogen resistance in different plant species; and [4] a thaumatin-like protein gene, OSML15, belonging to the pathogenesis related (PR) genes and which was shown to confer resistance to several soil-borne pathogens in tomato. Antisense repression of MKK1, WAT1, and SK23, as well as the overexpression of OSML15, was successfully achieved in the potato cultivar ‘Désirée’ and three lines from each type of transgenic plants selected for Ralstonia tests planned to be performed in the near future.