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The next-generation convergent microsystems, based on system-on-package (SOP) technology, require up-front system-level design-for-reliability approaches and appropriate reliability assessment methodologies to guarantee the reliability of digital, optical, and radio frequency (RF) functions, as well as their interfaces. Systems approach to reliability requires the development of: i) physics-based reliability models for various failure mechanisms associated with digital, optical, and RF Functions, and their interfaces in the system; ii) design optimization models for the selection of suitable materials and processing conditions for reliability, as well as functionality; and iii) system-level reliability models understanding the component and functional interaction. This paper presents the reliability assessment of digital, optical, and RF functions in SOP-based microsystems. Upfront physics-based design-for-reliability models for various functional failure mechanisms are presented to evaluate various design options and material selection even before the prototypes are made. Advanced modeling methodologies and algorithms to accommodate material length scale effects due to enhanced system integration and miniaturization are presented. System-level mixed-signal reliability is discussed thorough system-level reliability metrics relating component-level failure mechanisms to system-level signal integrity, as well as statistical aspects.