Flexible packaging has many advantages in the food industry, arising from low weight, formability, multilayer complexity and cost. Heat sealing is a very efficient technique to close flexible food packaging. Currently, many thermoplastic materials are used in seal layers. A seal can be formed when these materials are heated and brought into contact; thereafter, polymer chains diffuse across the seal interface and entangle. Hydrogen bonds, polar and ionic interactions are molecular forces that can come into play, depending on the thermoplastic materials that are used in the seal layer. Bonds between identical polymers, referred to as autohesion, are formed in pouch applications (e.g., horizontal and vertical form-fill-seal packages). In lidding applications, the flexible film is sealed to a rigid cup, tray or bottle, whereby bonds can be formed between non-identical polymers because the materials are often provided by different suppliers. All heat seal technologies imply heating of seal layers but differ in the heating principle. In the food industry and in most scientific seal studies, the seals of mono-and multilayered packaging are mainly formed by conductive heating. Recently, the use of emerging technologies, such as ultrasonic and laser heating, is increasingly described in recent papers. Applied seals are characterized by strength after a specified cooling time. Immediately after heating, this strength is referred to as hot tack. A good seal performance is crucial to guarantee food safety and quality. Besides strength, tightness is important to prevent food degradation, caused by microorganisms and external gases, and to keep aromatic gases inside the package. This review aims to give a literature overview that can support stakeholders in the food industry to improve and optimize the material selection in flexible packaging, in order to obtain seals with desired tightness and strength. Heat seal studies on materials and seal technology of flexible food packaging, such as pouches and lidding films, are considered. Scientific data are categorized from a materials' perspective, based on chemical structure, which is revealed by chemical and thermal analysis. A majority of the seal studies is categorized in a first section on polyolefins as seal layers. The following sections describe the seal functionality of (i) ethylene copolymers, such as ionomers; and (ii) polyesters, such as poly (ethylene terephthalate), pol (lactic acid) and poly (butylene succinate). The role of plasticizers, fillers and other