Over the last decade, there is increasing evidence that the small airways, i. e. airways <2 mm in internal diameter, contribute significantly to the pathophysiology and clinical expression of asthma and chronic obstructive pulmonary disease (COPD). The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiological methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and side effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery. The availability of small-particle aerosols of corticosteroid, bronchodilator or their combination, enables a higher total lung deposition, better peripheral lung penetration, and provides added clinical benefit, compared to large-particle aerosol treatment. However, a number of questions remain unanswered on the pragmatic approach relevant in order for clinicians to consider the role of small airways directed therapy in the day-to-day management of their patients with asthma and COPD. We have thus tried to clarify the dilemmas, confusion, and misconceptions related to small airways directed therapy. To this end, we have systematically reviewed all studies on small-particle aerosol therapy in order to address the dilemmas, confusion, and misconceptions related to small airways directed therapy.