Chronic obstructive pulmonary disease (COPD) is a main cause of death due to interplaying factors, including comorbidities that interfere with symptoms and response to therapy. It is now admitted that COPD management should be based on clinical symptoms and health status and should consider the heterogeneity of patients’ phenotypes and treatable traits. This precision medicine approach involves a regular assessment of the patient's status and of the expected benefits and risks of therapy. The cornerstone of COPD pharmacological therapy is inhaled long-acting bronchodilation. In patients with persistent or worsened symptoms, factors likely to interfere with treatment efficacy include the patient's non-adherence to therapy, treatment preference, inhaler misuse and/or comorbidities, which should be systematically investigated before escalation is considered. Several comorbidities are known to impact symptoms, physical and social activity and lung function. The possible long-term side-effects of inhaled corticosteroids contrasting with their over-prescription in COPD patients justify the regular assessment of their benefits and risks, and de-escalation under close monitoring after a sufficient period of stability is to be considered. While commonly used in clinical trials, the relevance of routine blood eosinophil counts to guide therapy adjustment is not fully clear. Patients’ characteristics, which define phenotypes and treatable traits and thus guide therapy, often change during life, forming the basis of the concept of clinical trajectory. The application of individual trajectory-based management of COPD in clinical practice therefore implies that the benefit:risk ratio is regularly reviewed according to the evolution of the patient's traits over time to allow optimised therapy adjustments.