Biomedical and Health Informatics (BMHI) have been essential catalysts for achievements in medical research and healthcare applications over the past 50 years. These include increasingly sophisticated information systems and data bases for documentation and processing, standardization of biomedical data, nomenclatures, and vocabularies to assist with large scale literature indexing and text analysis for information retrieval, and methods for computationally modeling and analyzing research and clinical data. Statistical and AI techniques for decision support, instrumentation integration, and workflow aids with improved data/information management tools are critical for scientific discoveries in the - omics revolutions with their related drug and vaccine breakthroughs and their translation to clinical and preventive healthcare. Early work on biomedical image and pattern recognition, knowledge-based expert systems, innovative database, software and simulation techniques, natural language processing and computational ontologies have all been invaluable for basic research and education. However, these methods are still in their infancy and many fundamental open scientific problems abound. Scientifically this is due to persistent limitations in understanding biological processes within complex living environments and ecologies. In clinical practice the modeling of fluid practitioner roles and methods as they adjust to novel cybernetic technologies present great opportunities but also the potential of unintended e-iatrogenic harms which must be constrained in order to adhere to ethical Hippocratic norms of responsible behavior. Balancing the art, science, and technologies of BMHI has been a hallmark of debates about the field’s historical evolution. The present article reviews selected milestones, achievements, and challenges in BMHI education mainly, from a historical perspective, including some commentaries from leaders and pioneers in the field, a selection of which have been published online recently by the International Medical Informatics Association (IMIA) as the first volume of an IMIA History WG eBook. The focus of this chapter is primarily on the development of BMHI in terms of those of its educational activities which have been most significant during the first half century of IMIA, and it concentrates mainly on the leadership and contributions of John Mantas who is being honored on his retirement by the Symposia in Athens for which this chapter has been written.