Root-knot nematode (RKN) species are predominant pests of crops, attacking stone fruit crops Prunus spp. under Mediterranean climate conditions worldwide. Natural resistance for rootstock breeding is a control method that is gaining interest as an alternative to the highly toxic nematicides. This review first reports an outline of the root-knot nematodes parasitizing stone fruit crops and the Prunus species and rootstocks. It then describes the main sources of resistance detected among the Prunus germplasm and focuses on the major resistance genes identified and their characteristics (spectrum, durability, histological mechanism, effect of temperature, interaction with other pests and diseases, etc.). In peach, besides the RMia reference gene, the new genes PkMi and Mf, also located on chromosome 2, need to be characterized regarding their spectrum and relationship. The two other Prunus reference genes, Ma from plum (complete spectrum) and RMja from almond (more restricted spectrum), are orthologs that belong to a TIR-NB-LRR (TNL) cluster on chromosome 7. The review finally summarizes the positional cloning of the Ma gene and the characterization of its unique TNL structure, encompassing a five-times repeated post-LRR domain. Deciphering how this structure is functionally involved in Ma’s remarkable biological properties is a real challenge for the future.