In the informatics field, a formal ontology is a human- and computer-interpretable set of terms and relations that represent entities in a specific domain and how they relate to each other. Ontology provides a standardization and computer interpretability of the data, metadata, and knowledge. Hundreds of ontologies have been reported and widely used to support data integration, sharing, reproducibility, and computer-assisted data analysis. To better support the reproducibility and data FAIRness, the ontologies should be interoperable (i.e., interconnected in a computer-understandable format). However, it may not be easy to make interoperable ontologies. The “eXtensible Ontology Development” (XOD) principles and related XOD tools provide a solid and feasible strategy for efficient development of interoperable and reproducible ontologies. The four XOD principles are: (i) ontology term reuse, (ii) ontology semantic alignment, (iii) ontology design pattern (ODP) usage, and (iv) community extensibility. These principles were derived from our summary of many years’ successes in ontology development and related tool development. The XOD principles have been proven to be successful in biological and biomedical fields, and they have also been widely used in other areas such as pharmaceutical, financial, and transportation fields.