Over the last three decades hot-melt extrusion (HME) has emerged as an influential processing technology in developing molecular dispersions of active pharmaceutical ingredients (APIs) into polymers matrices and has already been demonstrated to provide time controlled, modified, extended and targeted drug delivery resulting in improved bioavailability [1, 2, 3, 4]. HME has now provided opportunity for use of materials in order to mask the bitter taste of active substances. Since industrial application of the extrusion process back in the 1930’s HME has received considerable attention from both the pharmaceutical industry and academia in a range of applications for pharmaceutical dosage forms, such as tablets, capsules, films and implants for drug delivery through oral, transdermal and transmucosal routes [5]. This makes HME an excellent alternative to other conventionally available techniques such as roll spinning and spray drying. In addition to being a proven manufacturing process, HME meets the goal of the US Food and Drug Administration's (FDA) process analytical technology (PAT) scheme for designing, analyzing as well as controlling the manufacturing process through quality control measurements during active extrusion process [6]. In this chapter we review the hot-melt extrusion technique, based on a holistic perspective of its various components, processing technologies as well as the materials and novel formulation design and developments to its varied applications in oral drug delivery systems.