The 'Research Agenda for General Practice/Family Medicine and Primary Health Care in Europe' summarizes the evidence relating to the core competencies and characteristics of the Wonca Europe definition of GP/FM, and its implications for general practitioners/family doctors, researchers and policy makers. The European Journal of General Practice publishes a series of articles based on this document. The previous articles presented background, objectives, and methodology, as well results on 'primary care management' and 'community orientation' and the person-related core competencies of GP/FM. This article reflects on the general practitioner's 'specific problem solving skills'. These include decision making on diagnosis and therapy of specific diseases, accounting for the properties of primary care, but also research questions related to quality management and resource use, shared decision making, or professional education and development. Clinical research covers most specific diseases, but often lacks pragmatism and primary care relevance. Quality management is a stronghold of GP/FM research. Educational interventions can be effective when well designed for a specific setting and situation. However, their message that 'usual care' by general practitioners is insufficient may be problematic. GP and their patients need more research into diagnostic reasoning with a step-wise approach to increase predictive values in a setting characterized by uncertainty and low prevalence of specific diseases. Pragmatic comparative effectiveness studies of new and established drugs or non-pharmaceutical therapy are needed. Multi-morbidity and complexity should be addressed. Studies on therapy, communication strategies and educational interventions should consider impact on health and sustainability of effects.