In the past decades, with the guidance of Moore’s law, the size of transistors has continuously shrunk, while chip performance and computational capabilities have steadily improved. The relentless revolution has driven the sustained development of 2D planar integrated circuits. However, as the integrated circuit (IC) industry advances, the electronics manufacturing sector is approaching the physical limit of traditional CMOS process, making it increasingly challenging to enhance performance through transistor scaling. According to the International Technology Roadmap for Semiconductors (ITRS), 3D packaging based on vertical interconnect stacking has emerged as a critical research direction in the “Post-Moore era.” 3D packaging stacks multiple chips or systems (e.g., image sensors, MEMS, RF modules, memory) vertically, enabling the creation of more compact, multifunctional, and intelligent systems. It offers effective solutions for emerging fields such as 5G, IoT, and AI. Primarily, 3D packaging methodologies include CoC, PoP/PiP, and 3D Through-Silicon Via (TSV)/Through-Glass Via (TGV) integration. Up to now, 3D packaging technology has been extensively researched by universities, research institutes, and packaging-testing companies. Nevertheless, several reliability challenges must be addressed before widespread adoption, such as heat accumulation due to high power density, coefficient of thermal expansion (CTE) mismatch in heterogeneous integration, and structural delamination. This chapter first outlines the current development status and key structural features of 3D packaging. It then introduces the failure modes and failure mechanisms of 3D packaging structures, covering reliability issues in 3D chip stacking, 3D package stacking, and TSV-based 3D integration. Finally, classic 3D packaging failure cases are introduced.