Enhanced abiotic stresses such as increased drought, elevated temperatures, salinity, and extreme weather phenomena severely affect major crops in the Mediterranean area, a 'hot spot' of climate change. Plants have evolved mechanisms to face stressful conditions and adapt to increased environmental pressures. Intricate molecular processes involving genetic and epigenetic factors and plant-microbe interactions have been implicated in the response and tolerance to abiotic stress. Deciphering the molecular mechanisms whereby plants perceive and respond to stress is crucial for developing strategies to counteract climate challenges. Progress in determining genes, complex gene networks, and biochemical pathways, as well as plant-microbiota crosstalk, involved in abiotic stress tolerance has been achieved through the application of molecular tools in diverse genetic resources. This knowledge could be particularly useful for accelerating plant improvement and generating resilient varieties, especially concerning woody perennial crops, where classical breeding is a lengthy and labor-intensive process. Similarly, understanding the mechanisms of plant-microbe interactions could provide insights into innovative approaches to facing stressful conditions. In this review, we provide a comprehensive overview and discuss the recent findings concerning the genetic, epigenetic, and microbial aspects shaping abiotic stress responses, in the context of enhancing resilience in important Mediterranean woody perennial fruit crops.