The seismic assessment of existing buildings has developed from traditional measures of performance that focused on ensuring life safety to incorporating the potential economic losses incurred over time. This paper considers the assessment of existing reinforced concrete (RC) frame buildings, typically load designed before the introduction of seismic design provisions around the 1970’s in Italy, and across the Mediterranean area. Issues on their seismic response quantification are first discussed, which include the development of collapse fragility functions and dispersion in structural response needed for loss estimation. The collapse fragility functions are compared to existing damage scales describing complete structural collapse and it is seen how by following a number of key guidelines proposed here, collapse fragility functions may be numerically developed in a relatively efficient and unequivocal manner. The level of dispersion in the drift response of infilled frames is investigated and is shown to be very sensitive to the location of infill failure and subsequent soft storey mechanism. Further discussion highlights how the choice of the intensity measure may also be a contributing factor that could be investigated in the future to provide more efficient estimates of structural response. Aspects relating to the loss estimation and retrofitting are discussed with the purpose of giving readers further insight on some of the potential impacts of different retrofitting decisions for infilled RC frames within the context of mitigating economic losses. Lastly, issues regarding the implementation of a seismic performance classification framework are highlighted and potential future refinements are outlined.