The inadequate seismic behaviour of the cladding panel connections of precast structures and the consequent failures occurred under recent earthquakes in Southern Europe showed that a revision of the technology and design philosophies adopted for this type of systems is necessary. To solve this problem, a general framework for the seismic design of precast structures based on innovative fastening systems of the cladding panels is proposed. In this framework, the stability of the cladding panels under seismic action is ensured by means of a dissipative system of connections in between the panels that allows to control the level of forces and to limit the displacements. The proposed connection systems consist of friction-based or plasticity-based devices inserted in between panels, that are connected to the structure through a statically determined arrangement. In this way, the panel-to-panel connections lead the cladding panels to become integral part of the whole façade, making it much stiffer up to the limit force associated with the friction threshold or yielding of the devices. Plasticity-based dissipative connectors to be inserted between columns and panels are also proposed and investigated. The technological aspects and design choices of materials and shapes leading to a stable hysteretic behaviour of the dissipative devices are discussed and subjected to experimental verification at Politecnico di Milano by means of monotonic and cyclic tests carried out on single devices, as well as on full scale two-panel structural sub-assemblies with dissipative connections. The silicone sealant, that is generally interposed in between the panels, is also mechanically characterised through experimental testing. Design guidelines for single devices are derived based on the interpretation of the experimental results. Capacity design procedures for structural sub-assemblies and systems are also developed based on the mechanical characteristics of the dissipative connectors. The efficiency of the proposed approach is demonstrated by means of non-linear dynamic analyses of typical precast frame-panel structural systems, as well as through a further experimental campaign carried out at ELSA Laboratory of the Joint Research Centre of the European Commission on a full-scale prototype of a precast building with cladding panels. This experimental program includes pseudo-dynamic and cyclic tests on structural assemblies provided with vertical and horizontal panels and different types of connection systems, including the friction-based panel-to-panel dissipative connections tested at Politecnico di Milano. Numerical simulation of the pseudo-dynamic and cyclic tests is performed to calibrate the modelling criteria provided in the design guidelines and to validate simplified procedures for the estimation of the maximum drift attained during a seismic event. The role of the diaphragm action on the efficiency of the proposed connection systems is finally investigated by means of dynamic nonlinear analyses carried out on a set of precast buildings with different plan geometry and distribution of the earthquake-resisting system. The results confirm the remarkable improvement of the seismic performance of precast structures based on the beneficial effects of dissipative cladding connections, which can provide suitable energy dissipation capacity and limit forces and displacements when the effectiveness of the horizontal diaphragms is ensured.