The INSPIRE project was dedicated to the study of physical processes and their effects in ionosphere which could be determined as earthquake precursors together with detailed description of the methodology of ionospheric pre-seismic anomalies definition. It was initiated by ESA and carried out by an international consortium. The full set of key parameters of the ionospheric plasma was selected based on the retrospective analysis of the ground-based and satellite measurements of pre-seismic anomalies. Using this classification the multi-instrumental database of worldwide relevant ionospheric measurements (ionosonde and GNSS networks, LEO-satellites with in situ probes including DEMETER and FORMOSAT/COSMIC ROC missions) was developed for the time intervals related to selected test cases. As statistical processing shows, the main ionospheric precursors appear approximately 5 days before the earthquake within the time interval of 30 days before and 15 days after an earthquake event. The physical mechanisms of the ionospheric pre-seismic anomalies generation from ground to the ionosphere altitudes were formulated within framework of the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) model. The processes of precursor’s development were analyzed starting from the crustal movements, radon emission and air ionization, thermal and atmospheric anomalies, electric field and electromagnetic emissions generation, variations of the ionospheric plasma parameters, in particular vertical TEC and vertical profiles of the electron concentration. The assessment of the LAIC model performance with definition of performance criteria for earthquake forecasting probability has been done in statistical and numerical simulation domains of the Global Electric Circuit. The numerical simulations of the earthquake preparation process as an open complex system from start of the final stage of earthquake preparation up to the final point–main shock confirms that in the temporal domain the ionospheric precursors are one of the most late in the ...