The science of adhesives and adhesion for structural connections has undergone significant development during the last few decades - and successfully so in a wide variety of industries. Recent applications of structural bonding are being adopted in the construction sector, and particularly in bridge engineering for the rehabilitation and strengthening of existing structures or new constructions. Knowledge concerning structural bonding, however, is rarely specifically intended for the civil engineering domain, where, unlike in aerospace and automotive applications, in situ conditions involve the manufacturing control of often large bonding surfaces and use of cold-curing adhesives, particularly epoxy-based, under uncontrolled weather conditions. Various environmental factors may influence the durability of a bonded bridge connection throughout the long-term service life, with concurrent effects on the development of the physical and mechanical properties of the adhesive that participates in the structural integrity of the joint. In parallel, the curing degree of cold-curing adhesives, which is not completely developed particularly in the earlier age, continues to govern both the physical and mechanical responses of the adhesive. Despite a significant amount of current research on the long-term characterization of cold-curing structural adhesives, precise information concerning the reliability of these materials over their long-term service life, of up to 100 years in the case of bridge applications, is yet to be compiled in order to encourage their wider use by bridge engineers. The objective of this work, based on an extensive experimental campaign followed by analytical and numerical approaches, has therefore been to investigate the long-term effects of curing and aging on the property development of a cold-curing epoxy adhesive under exposure to environmental and cyclic mechanical actions like those typically encountered in bridge applications. Investigations have been conducted concerning adhesive exposures under dry conditions, in normal cases of sealed bridge joints, and wet conditions, when the sealing is distorted or the adherends are permeable, or cases of alkaline attacks when the adhesive is in contact with cementitious substrates. Physical aging (densification) in the earlier age and curing continuation in the later age govern the physical and mechanical property development in the case of dry environments, while curing effects are compensated by plasticization in the later age in wet environments. A 30% reduction of the tensile E-modulus and strength over a 100-year life in immersed conditions has been predicted, but is found to be fully reversible upon drying. The adhesive’s exposure to alkaline solutions had no detrimental effect. The adhesive environmentally aged over periods of up to 100 years by accelerated conditioning is capable of attaining fatigue lives of ca. 10 million cycles, typical for a bridge lifetime, without failure at maximum cyclic stress levels of higher than 5 MPa. The results of this study are implemented in bridge design concepts and practical recommendations are provided. The moisture ingress into the adhesive layer of two typical bridge joints has been numerically investigated and the corresponding degradation of mechanical properties is derived. Depending on the joint type, this effect may be critical, as for example in the case of the thin bondlines of CFRP strengthening elements.