This work addresses the challenges in design of heat integrated low-temperature separation processes. A novel, systematic and robust methodology is developed, which contributes to the design practice of heat-integrated separation sequence and the refrigeration system in the context of low-temperature separation processes. Moreover, the methodology exploits the interactions between the separation and refrigeration systems systematically in an integrated design context. The synthesis and optimisation of heat-integrated separation processes is complex due to the large number of design options. In this thesis, task representation is applied to the separation system to accommodate both simple and complex distillation columns. The stream conditioning processes are simulated and their associated costs are included in the overall cost of the process. Important design variables in separation systems, such as the separation sequence, type and operating conditions of the separation units (e.g. the operating pressure, feed quality and condenser type) are optimised. Various refrigeration provision strategies, such as expansion of a process stream, pure and mixed multistage refrigeration systems and cascades of multistage refrigeration cycles, are considered in the present work. A novel approach based on refrigeration system database is proposed, which overcomes the complexities and challenges of synthesis and optimisation of refrigeration systems in the context of low-temperature separation processes. The methodology optimises the key design variables in the refrigeration system, including the refrigerant composition, the number of compression stages, the refrigeration and rejection temperature levels, cascading strategy and the partition temperature in multistage cascaded refrigeration systems. The present approach has selected a matrix based approach for assessing the heat integration potentials of separation and refrigeration systems in the screening procedure. Non-isothermal streams are not considered isothermal and stream splitting and heat exchangers in series are taken into account. Moreover, heat integration of reboiler and condenser of a distillation column through an open loop heat pump system can be considered in this work. This work combines an enhanced simulated annealing algorithm with MILP optimisation method and develops a framework for simultaneously optimising different degrees of freedom in the heat integrated separation and refrigeration processes. Case studies extend the approach to the design of heat integrated separation sequences in above ambient temperature processes. The robustness of the developed framework is further demonstrated when it is utilised to design the LNG and ethylene plant fractionation trains.