The sleep medicine community has increasingly recognized the necessity that clinical care be based on high-quality levels of evidence. Although research supports a favorable influence of positive airway pressure (PAP) therapy on risk for significant adverse outcomes in patients with severe obstructive sleep apnea–hypopnea (OSAH), well-designed trials are still required to elucidate the effect of PAP on health, quality of life, and economic risks in patients with milder OSAH. Similarly, although there is strong evidence supporting various PAP titration strategies and PAP modalities in patients with severe OSAH without significant medical and psychiatric comorbidities, there is insufficient high-level evidence assessing and comparing the clinical efficacy and health care cost implications of various titration paradigms and various PAP modalities in individuals with milder OSAH and those with comorbid conditions. For ethical and other reasons, it may not be possible to apply a randomized controlled design to address all questions. However, whichever design is employed, it must be rigorously developed with attention to all potential confounders with adequate power to provide compelling, high-quality evidence.