Simple SummaryGlobally, honey bees are exposed to many challenges, such as theVarroa destructormite and various viruses, which lead to massive losses. It is generally believed that African honey bees are more resilient and better able to cope with these stressors. This study examined some molecular markers that may be associated with this resilience. Higher resistance to the varroa mite could be related to better olfactory sensing. Higher gene expression levels of the odorant binding protein OBP14 in the antennae of Ethiopian honey bees suggest that reproducing mites might be better detected and cleaned. Resistance or tolerance to viruses could be attributed to a better functioning antiviral RNAi system. Several genes involved in this pathway are upregulated and are positively correlated with the viral load in honey bees. Both mechanisms may contribute to the resilience of African bees to varroa infestation and viral infection.AbstractVarroa destructormites and the viruses it vectors are two major factors leading to high losses of honey bees (Apis mellifera) colonies worldwide. However, honey bees in some African countries show resilience to varroa infestation and/or virus infections, although little is known about the mechanisms underlying this resilience. In this study, we investigated the expression profiles of some key molecular markers involved in olfactory sensing and RNA interference, as these processes may contribute to the bees’ resilience to varroa infestation and virus infection, respectively. We found significantly higher gene expression of the odorant binding protein, OBP14, in the antennae of Ethiopian bees compared to Belgian bees. This result suggests the potential of OBP14 as a molecular marker of resilience to mite infestation. Scanning electron microscopy showed no significant differences in the antennal sensilla occurrence and distribution, suggesting that resilience arises from molecular processes rather than morphological adaptations. In addition, seven RNAi genes were upregulated in the Ethiopian honey bees and three of them—Dicer-Drosha,Argonaute 2, andTRBP2—were positively correlated with the viral load. We can conclude that the antiviral immune response was triggered when bees were experiencing severe viral infection and that this might contribute to the bees’ resilience to viruses.