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The present PhD Thesis was developed in the framework of several Research Programs in which the Department of Aerospace Engineering at University of Pisa was directly involved, with the general aim to characterized the fatigue behavior of conventional and innovative joints typically employed in the production of aeronautical and aerospace structures. Correct predictions could obviously improve design of optimized structures, maintaining or increasing actual safety levels: but the separate or synergic effects of several parameters must be considered to correctly reproduce structure in-service behavior. The logic-flow adopted for each aspect analyzed in the present research had his origin on a consistent database of experimental data, ranging from general mechanical properties material characterization to strain gauge evaluations of associated stress fields, moving toward a more comprehensive description of the faced problem by means of Finite Elements simulations, to finally reach, by fracture mechanics codes, a generalized model. Attention was mainly focused on parameters characterized by a lack of information in literature or unsatisfactory prediction models. Among others aspects, the effect of Secondary Bending on conventional longitudinal fuselage joints was deeply investigated, bringing to a clear improvement of fracture mechanics software. Furthermore were analyzed different technologies capable of decidedly improve joint performance in a standard architecture. Processes as Interference Fit, Split Sleeve Cold Working, StressWave and ForceMate were demonstrated to significantly retard crack initiation and propagation in critical points, introducing beneficial stress fields. Besides currently great efforts are made by the aerospace International Community to investigate the possibility of replacing standard joining methodology by new technologies which are expected to provide considerable weight saving and cost reductions, incorporating integral structures in aircraft constructions. The more promising one, the ‘Friction Stir Welding’, was widely explored during the present activity in different aeronautical and aerospace applications, demonstrating to be a very robust and reliable process.