A climate-neutral building standard for new and existing buildings is essential for achieving the global climate protection targets. In the research project “sEnSys”, a holistic energy supply concept for multi-storey residential buildings (MSRB), that achieve energy and climate neutrality, is being developed and implemented in a real demonstration building. The concept focuses on energy-efficient, resilient and smart building technologies, a predictive control strategy and cost-effective operation via suitable operator models. When retrofitting a MSRB, a number of well-established energy supply concepts are conceivable, which differ in terms of the heat source and heat generator as well as the additional system technologies required. The retrofitted building envelope also plays a decisive role in increasing the overall system efficiency. Thus, a large number of hydraulics and building variants can be derived from these aspects. This paper presents an energetic, economic and ecological assessment of retrofitting a MSRB based on different energy supply concepts. Different retrofit standards for the building envelope with different heat generators and heat sources (heat pumps, pellet-fuel boilers or combined heat and power plants) are considered, which were supplemented with additional system technologies (photovoltaics, ventilation). Calculations were carried out in accordance with DIN/TS 12831–1 and DIN V 18599 in order to evaluate the energy consumption and the ecological footprint. The economic viability of the retrofit is examined over a period of 25 years, taking into account both subsidized and non-subsidized variants. A digital BIM-IFC model forms the basis for all calculations and simulations.