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Tricuspid regurgitation (TR) rarely exists as an isolated condition and is most frequently secondary due to heart failure (HF), or atrial fibrillation, with prevalent extracardiac comorbidities. Morphological assessment of the anatomy and severity of TR, together with evaluation of symptoms, currently drives interventional approaches, yet a more holistic integration of causal and contributing comorbid conditions might further improve outcomes. The present review explores such a pathophysiology-driven holistic approach to interpret functional changes and symptomatic burden in patients with TR. It focuses on acknowledging the dynamic nature of TR, but most importantly the bidirectional crosstalk between TR and HF, as well as other organ systems that might drive symptoms and prognosis, but also TR progression. Assessment of TR is ideally performed after optimizing the treatment of interfering comorbidities and correcting volume overload to isolate the true effects of the TR itself. Invasive hemodynamic assessment, portal vein Doppler, and liver stiffness measurements may offer useful information in clinical decision-making. When TR is identified as the primary driver of disease, or if it is strongly interacting with concomitant diseases, more aggressive therapeutic approaches may be pursued. In contrast, when it is more a consequence of the underlying HF, the right expectations in terms of symptomatic improvement and prognosis should be set. This framework may help to identify patients who are the most likely to benefit from TR interventions, while acknowledging the complexity of their clinical picture in the context of HF.