Successful 3D printability depends on various critical parameters. During formulation, ensuring the stability of the active pharmaceutical ingredient (API) while processing and within the 3D-printed dosage forms entails critical components. The major challenge in stability is preserving the API’s physical (crystalline or amorphous) nature. While hot-melt extrusion (HME) offers amorphization of the API, the challenge lies in maintaining the active’s physical and chemical stability, such as the risk of degradation at elevated temperatures. Balancing API-polymer miscibility and leveraging non-covalent interactions become integral strategies for stability. Comprehensive analytical methodologies and real-time monitoring techniques provide valuable tools for stability assessment during formulation and product development. By selectively incorporating plasticizers, antioxidants, and optimal processing parameters, coupled with stringent storage protocols, the journey toward consistent, top-tiered 3D-printed pharmaceutical products is introduced and discussed within this chapter.