The paper addresses the application of effective tools for investigating structural integrity under earthquake loading, namely experimental testing, computer analysis and field data collection, and their combination. In particular, the application of hybrid (experimental-analytical) distributed (using several sites) simulation, hereafter referred to as HDS, to investigate seismic response of complex systems is presented. After briefly reviewing and comparing approaches of field surveys, testing, analysis and hybrid simulation, the paper deals with five applications where at least two of the three tools have been successfully applied. The collapse of the I-880 (Cypress Viaduct) during the Loma Prieta (California) earthquake of 1989 was investigated analytically following field observation of the failure modes. A plausible mechanism was postulated based on advanced analysis and supported by field data. Analytical studies aimed at quantifying the demand imposed on steel moment frames in the Northridge (California) earthquake of 1994 pointed towards a possible contribution of vertical beam modes to the increased rotational demand imposed on connections, leading to their failure. Next, issues of irregularity and lack of seismic detailing in RC buildings, repeatedly observed to be a major contributor to damage, are studied at full scale using laboratory testing, supported by advanced analysis to steer the model design and tune the level of input motion. Reinforced concrete bridges are also studied, using advanced analysis and field observations to investigate the partial collapse of a ramp structure part of the Santa Monica Freeway (I-10). Finally, two examples of applications of hybrid distributed simulation (HDS) are presented, one of which is a continuation of the steel moment frames analytical investigation. It is emphasized that it is only through integrating the available investigation tools that the response of complex systems may be understood, leading to more economical and safer built environments in regions subjected to earthquakes.