Rationale: Research suggests that respiratory and cardiovascular drugs can ameliorate the rate of lung function decline. Objectives: To investigate the impact of respiratory and cardiovascular pharmacotherapy on lung function trajectories in the general population. Methods: Repeated spirometry was performed in the Rotterdam Study, a population-based cohort of adults aged ≥45 years. Exposure to long-acting beta2-agonists (LABA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), cardioselective beta-blockers, calcium channel blockers, ACE-inhibitors, angiotensin-II receptor blockers, and statins was quantified from pharmacy records to account for therapy adherence. Propensity-score matching and multinomial logistic regression were performed to model medication effects on lung function trajectories, which were previously identified based on FEV 1 and FVC patterns. Models were additionally stratified by genetic variation in each drug target. Measurement and Main Results: Among 3,783 individuals, 2,974 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Exposure to LABA (odds ratio (OR) =1.09 [95%-CI: 1.03-1.16] per 10% increase in exposure), ICS (OR=1.08 [95%-CI: 1.02-1.14]), and statins (OR=1.04 [95%-CI: 1.02-1.06]) significantly increased the odds of being an improver compared to a normal decliner. Beta 1 -blocker use was associated with higher odds of being a rapid decliner (OR=1.04 [95%-CI: 1.00-1.09]), which was driven by incident users. Pharmacogenetic analysis suggests that the effects of LABA, ICS, and beta 1 -blockers are dependent on genetic variation in their drug targets. Conclusions: Our study suggests that LABA, ICS, and statins may favorably modulate lung function trajectories in adults, while initiation of beta 1 -blockers was associated with rapid lung function decline.