Old Cairo, also known as Islamic Cairo, is a UNESCO World Heritage Site representing a rich tapestry of history and culture. Today, among various significant aspects, its cultural heritage necessitates the elaboration of a proactive conservation strategy, which should take advantage of the intrinsic support provided by the efforts documented in the literature that have been made in several scientific fields, disciplines, and directions over the years. Most historic religious monumental buildings in Old Cairo, in particular, not only face the effects of local seismic hazards, which are emphasized by damage by past earthquakes, but also suffer the consequences of several influencing parameters that are unique to the Cairo city context. In this sense, it is known that the structural retrofitting of these monumental buildings requires sound knowledge of technical details and criticalities, based on inspections, numerical simulations, the in-field integration of technologies, and laboratory tests. Many other gaps should also be addressed, and a sound conservation strategy should be elaborated on the basis of a multi-target approach, which could account for the structural engineering perspective but also contextualize the retrofit within the state of the art and the evolution of past events. This is the target of the contemporary “Particular Relevance” bilateral Italy–Egypt “CoReng” project, seeking to define a multidisciplinary strategy for conserving Old Cairo’s cultural heritage and focusing primarily on the case study of the Religions Complex. To this end, a review analysis of major oversights and challenges relating to historic monuments in Old Cairo is presented in this paper. Learning from past accidents and experiences is, in fact, the primary supporting basis for elaborating new operational steps and efficient approaches to mitigating challenges and minimizing the consequences of emergency events. As such, this review contribution specifically focuses on the structural vulnerability of historic monumental buildings in Old Cairo, reporting on past efforts, past strategy proposals, research experiences, and trends.