Proteins belonging to the pathogenesis-related class 10 (PR-10), especially the main birch pollen allergen Bet v 1, are members of one of the most clinically significant groups of plant panallergens. Their highly conserved spatial structure provides the molecular basis for a high IgE cross-reactivity, leading to the pollen-food allergy syndrome (PFAS) that affects millions of people worldwide. This comprehensive overview of PR-10 allergens integrates their structural biology with the latest advances and future directions in immunotherapy. Here, we analyze molecular determinants of cross-reactivity, discuss mechanisms of allergen-specific immunotherapy (AIT), and critically evaluate its current state for the birch pollen and related food allergies, highlighting limitations of conventional extract-based vaccines in treating PFAS. Finally, we review the most promising strategies that have entered clinical trials, including T-cell epitope-based peptide vaccines, recombinant hypoallergenic derivatives, and innovative hapten-carrier vaccines, designed to induce polyclonal IgG responses against multiple clinically relevant IgE epitopes of several PR-10 allergens. All data collected in this review not only represents current understanding of PR-10 allergic properties but also highlights the need for further research into molecular mechanisms of the PR-10-related allergy and development of next-generation immunotherapy strategies.