Obstructive sleep apnea (OSA) is a common condition that is increasing in prevalence worldwide. Untreated OSA has a negative impact on health-related quality of life and is an independent risk factor for cardiovascular diseases. Despite available data suggesting that cardiovascular risk might differ according to clinical phenotypes and comorbidities, current approaches to OSA treatment usually take a “one size fits all” approach. Identification of cardiovascular vulnerability biomarkers and clinical phenotypes associated with response to positive airway pressure (PAP) therapy could help to redefine the standard treatment paradigm. The new PAP-RES (PAP-RESponsive) algorithm is based on the identification of OSA phenotypes that are likely to impact therapeutic goals and modalities. The paradigm shift is to propose a simplified approach that defines therapeutic goals based on OSA phenotype: from a predominantly “symptomatic phenotype” (individuals with high symptom burden that negatively impacts on daily life and/or accident risk or clinically significant insomnia) to a “vulnerable cardiovascular phenotype” (individuals with comorbidities [serious cardiovascular or respiratory disease or obesity] that have a negative impact on cardiovascular prognosis or a biomarker of hypoxic burden and/or autonomic nervous system dysfunction). Each phenotype requires a different PAP therapy care pathway based on differing health issues and treatment objectives.