Changing expectations of general practice are driven by diverse forces including an increased demand for chronic care. General practice care of chronic disease and illness straddles a wide spectrum of disciplines. However, political, health care, and research structures maintain discrete discipline orientated research. 'Objective' evidence, from quantitative paradigms, about disease, treatment and services predominate over 'subjective' evidence based upon understandings, for example, about how people live with chronic illness. Transdisciplinary approaches are desirable to provide synthesis of evidence across these paradigms to inform and evaluate the complexity of generalism in clinical care. However, transdisciplinarity is only feasible if it both respects disciplinary traditions, yet challenges underlying assumptions about knowledge creation. Inductive processes and open rather than closed systems provide mechanisms for this process. Transdisciplinarity needs to operate at levels of abstraction where there is commonality, typically at the level of the research question and the resultant formulation of theory and knowledge to inform policy or practice. Multidisciplinary teams and transdisciplinary trained researchers with meta-theoretical frameworks that facilitate these conceptual and practicable linkages are discussed. Major challenges to transdisciplinary approaches remain, not only because of their newness, but because of different theoretical traditions, and with the current structures of disciplines, evaluation and research funding and training. We need reflexive integrated general practice research in response to the ever-changing and multi-dimensional nature of health care. Despite fluidity and evolution, research processes that are mainly driven by expediency, may not best serve the needs of those with chronic illness or general practice.