This chapter explores the possibility of building a unified assessment methodology for software reliability and security. The fault injection methodology originally designed for reliability assessment is extended to quantify and characterize the security defense aspect of native applications. Native application refers to system software written in C/C++ programming language. Specifically, software fault injection is used to measure the portion of injected software faults caught by the built-in error detection mechanisms of a target program (e.g., the detection coverage of assertions). To automatically activate as many injected faults as possible, a gray box fuzzing technique is used. Using dynamic analyzers during fuzzing further helps us catch the critical error propagation paths of injected (but undetected) faults, and identify code fragments as targets for security hardening. Because conducting software fault injection experiments for fuzzing is an expensive process, a novel, locality-based fault selection algorithm is presented. The presented algorithm increases the fuzzing failure ratios by 3–19 times, accelerating the speed of experiment. The case studies use all the above experimental techniques in order to compare the effectiveness of fuzzing and testing, and consequently assess the security defense of native benchmark programs.