Certain ontology and epistemology perspectives are most relevant to human systems’ enquiry. These are derived from a synergy of insights from theories of autopoiesis, interpersonal neurobiology and complexity. Ontology has implications for our comprehension of the nature of human systems: 1/ Human systems are embodied and situated, exhibiting selforganising and emergent properties; 2/ Human experience is personal but not private, it is born in the interactions with the environment, and is validated by the human structure; 3/ Changes in human structure are necessarily subservient to conservation of autopoiesis, i.e. self-production and maintaining life. The epistemological implications deem ontology and epistemology as mutually informative in human enquiry; the thrust of this article. Our knowledge is limited by our capabilities of awareness. The quality of perception interlinks with cultivating awareness and intentionality for maintaining wellbeing, i.e. sustaining life-enhancing conditions. The concept of ‘wellbeing informatics’ is used to outline a tangible approach to evaluating wellbeing.