Most potato cultivars are susceptible to late blight disease caused by the oomycete pathogen Phytophthora infestans. Here we report that the genetic loss of host susceptibility is a new source of resistance to prevent or diminish pathogen infection. Previously, we showed that RNAi-mediated silencing of the potato susceptibility (S) genes StDND1, StDMR1, and StDMR6 leads to increased late blight resistance. The mechanisms underlying this S-gene-mediated resistance have thus far not been identified. In this study, we examined the infection process of P. infestans in StDND1-, StDMR1-, and StDMR6-silenced potato lines. Microscopic analysis showed that penetration of P. infestans spores was hampered in StDND1-silenced plants. In StDMR1- and StDMR6-silenced plants, P. infestans infection was arrested at a primary infection stage by enhanced cell death responses. Histochemical staining revealed that StDMR1- and StDMR6-silenced plants display elevated ROS levels in cells at the infection sites. Resistance in StDND1-silenced plants, however, seems not to rely on a cell death response as ROS accumulation was found to be absent at most inoculated sites. Quantitative analysis of marker gene expression suggests that the increased resistance observed in StDND1- and StDMR6-silenced plants relies on an early onset of salicylic acid- and ethylene-mediated signaling pathways. Resistance mediated by silencing StDMR1 was found to be correlated with the early induction of salicylic acid-mediated signaling. These data provide evidence that different defense mechanisms are involved in late blight resistance mediated by functional impairment of different potato S-genes.