Bronchoalveolar lavage and lung biopsy (LBx) are helpful in patients with connective tissue diseases (CTD) and interstitial lung diseases (ILD) regardless of cause, including infectious, noninfectious, immunologic, or malignant. The decision whether to perform only bronchoalveolar lavage (BAL), and eventually a subsequent LBx in case of a nondiagnostic lavage, or one single bronchoscopy combining both sampling methods depends on the clinical suspicion, on patient’s characteristics (e.g. increased biopsy risk) and preferences, and on the resources and biopsy techniques available locally (e.g. regular forceps versus cryobiopsy). In CTD-ILD, BAL has major clinical utility in excluding infections and in the diagnosis of specific patterns of acute lung damage (e.g. alveolar hemorrhage, diffuse alveolar damage, and organizing pneumonia). LBx is indicated to exclude neoplasm or diagnose lymphoproliferative lung disorders that in CTD patients are more common than in the general population. Defining BAL cellularity and characterizing the CTD-ILD histopathologic pattern by LBx can be helpful in the differential diagnosis of cases without established CTD [e.g. ILD preceding full-blown CTD, interstitial pneumonia with autoimmune features (IPAF)], but the prognostic and theragnostic role of those findings remains unclear. Few studies in the pretranscriptomics era have investigated the diagnostic and prognostic role of BAL and LBx in CTD-ILD, and it is reasonable to hypothesize that future studies conducted applying innovative techniques on BAL and LBx might open new and unexpected avenues in pathogenesis, diagnosis, and treatment approach to CTD-ILD. This is particularly desirable now that a new drug treatment era is emerging, in which we have more than one therapeutic choice (immunosuppressive agents, antifibrotic drugs, and biological agents). We hope that future research will pave the path toward precision medicine providing data for a more accurate ILD-CTD endotyping that will guide the physicians through targeted therapeutic choices, rather than to the approximative approach ‘one drug fits them all’.