The development and use of cultivars that are genetically resistant to viruses is an efficient strategy to tackle the problems of virus diseases. Over the past two decades, the model plant Arabidopsis thaliana has been documented as a host for a broad range of viral species, providing access to a large panel of resources and tools for the study of viral infection processes and resistance mechanisms. Exploration of its natural genetic diversity has revealed a wide range of genes conferring virus resistance. The molecular characterization of some of these genes has unveiled resistance mechanisms distinct from those described in crops. In these respects, Arabidopsis represents a rich and largely untapped source of new genes and mechanisms involved in virus resistance. Here, we review the current status of our knowledge concerning natural virus resistance in Arabidopsis. We also address the impact of environmental conditions on Arabidopsis-virus interactions and resistance mechanisms, and discuss the potential of applying the knowledge gained from the study of Arabidopsis natural diversity for crop improvement.