Plants have evolved a limited repertoire of NB-LRR disease resistance (R) genes to protect themselves against a myriad of pathogens. This limitation is thought to be counterbalanced by the rapid evolution of NB-LRR proteins, as only few sequence changes have been shown to be sufficient to alter resistance specificities towards novel strains of a pathogen. However, little is known about the flexibility of NB-LRR genes to switch resistance specificities between phylogenetically unrelated pathogens. To investigate this, we created domain swaps between the close homologs Gpa2 and Rx1, which confer resistance in potato to the cyst nematode Globodera pallida and Potato virus X (PVX), respectively. The genetic fusion of the CC-NB-ARC of Gpa2 with the LRR of Rx1 (Gpa2CN/Rx1L) resulted in autoactivity, but lowering the protein levels restored its specific activation response including extreme resistance to PVX in potato shoots. The reciprocal construct (Rx1CN/Gpa2L) showed a loss-of-function phenotype, but exchange of the first 3 LRR repeats of Rx1 was sufficient to regain a wild type resistance response to G. pallida in the roots. These data demonstrate that exchanging the recognition moiety in the LRR is sufficient to convert extreme virus resistance in the leaves into mild nematode resistance in the roots, and vice versa. In addition, we show that the CC-NB-ARC can operate independently of the recognition specificities defined by the LRR domain, either above or belowground. These data show the versatility of NB-LRR genes to generate resistances to unrelated pathogens with completely different lifestyles and routes of invasion.