The seismic vulnerability and risk assessment of infrastructure and utility systems are essential to prevent or mitigate sufficiently the negative consequences, implement resilience management strategies, and recover efficiently after a major earthquake. In a complex urban environment, having multiple interacting and interdependent infrastructures becomes even more important. Earthquake hazards not only affect a single asset, but also their impact is much greater because of the inter- and intra-dependences among various infrastructure, utility systems, and lifelines. Therefore, we urgently need efficient tools to quantify and assess the systemic vulnerability and risk of urban infrastructure and utility systems. This is a challenging topic that is nowadays receiving more attention from the research community, the industry domain, and the policymakers. This paper aims to review the available modelling approaches and tools for the seismic risk analysis of interconnected systems, including advantages and limitations. It focuses in particular on the European funded SYNER-G project that encompasses interdependencies, delivers a holistic methodology, and implements a comprehensive framework based on the Object-Oriented Modelling paradigm. The capacities of the SYNER-G framework are illustrated through a selected application regarding the seismic risk analysis of interconnected infrastructure and utility systems in the city of Thessaloniki, Greece. Among other aspects, the paper discusses hazard modelling issues of the two common approaches, the probabilistic and the scenario-based procedure and illustrates in a specific example the impact of mitigation strategies, based on their effect on the performance of the interconnected systems and the overall loss reduction. The integration of interdependencies into the risk analysis and resilience strategies facilitates a better understanding of critical infrastructure operation and enables well-informed proactive and reactive decision-making and efficient disaster risk management, by infrastructure owners and operators, insurance companies, consulting agencies, and local authorities.