Purpose of Review <p>This review aims to provide an updated overview of the clinical management of heart failure and comorbidities in transthyretin amyloid cardiomyopathy (ATTR-CM). We sought to address key unanswered questions and current uncertainties regarding treatment response, prognosis, and optimization of care in this complex population.</p> Recent Findings <p>Once considered rare, ATTR-CM is now increasingly recognized due to greater awareness and the possibility of non-invasive diagnosis. Patients are often identified at earlier stages, with lower mortality than historically observed. Disease-modifying therapies with proven efficacy in randomized trials are now available, yet many patients experience disease progression. In real-world practice, ATTR-CM patients are typically older and have multiple cardiac and extracardiac comorbidities, often representing exclusion criteria of clinical trials, which may influence treatment response and efficacy.</p> Summary <p>Modern management of ATTR-CM should integrate heart failure treatment with tailored approaches to comorbidity care. Earlier diagnosis, real-world evidence, and strategies for patients outside trial populations will be essential to improve prognosis and guide future research.</p>