The paradigm of patent foramen ovale (PFO)-associated syndrome management has been significantly influenced by seminal guidance documents, which underscore the importance of multidisciplinary collaboration and individualized decision-making frameworks. Since the first European Position Papers published in 2018 and 2021, these documents have provided a structured template for the evaluation and treatment of cryptogenic stroke, desaturation syndromes, decompression sickness (DCS), and migraine with aura, thereby facilitating a more nuanced approach to patient care. A critical examination of the current indications for PFO closure reveals a notable lack of evolution over the past 5 years, with recommendations largely mirroring those previously established. Specifically, PFO closure is presently advocated for patients aged 18–60 years with cryptogenic stroke and high-risk features, as well as for select individuals over 60 years following exhaustive exclusion of alternative etiologies. Conversely, PFO closure remains the standard of care for severe desaturation syndromes, is selectively employed for PFO-related DCS, and is considered investigational for migraine with aura. The inherent heterogeneity of PFO-associated syndromes poses a significant challenge to the development of precision-based treatment strategies, highlighting the need for innovative, multidimensional approaches that integrate advanced technologies and personalized algorithms to elucidate distinct phenotypic profiles and optimize therapeutic outcomes. Ultimately, the stagnation of current treatment paradigms underscores the imperative for continued research and clinical innovation, with a focus on refining patient selection criteria and enhancing the efficacy and safety of interventions such as PFO closure.