Clinical genomics/metagenomics is a rapidly developing field and it makes genomic, transcriptomic, and epigenomic evaluations of clinically relevant samples possible due to decreasing sequencing costs and large volumes of sequence datasets. Applications of comprehensive protocols for clinical metagenomic analysis is rapidly moving from the research laboratories to the clinical laboratories in healthcare settings. It has not only improved medical interventions but also continue to contribute to precision treatments. In this dissertation, I am going to discuss (i) the applications of clinical genomics/metagenomics protocols in several clinical cases of infections and (ii) the application of comparative genomics in Mycobacterium riyadhense clinical isolates which provide insights into ancestry and adaptive evolution in MTBC (Mycobacterium tuberculosis complex); The research questions are systematically addressed in four chapters. Briefly, Chapter 1 provides a brief introduction of conventional clinical microbiology and clinical metagenomics and a research summary of the thesis; Chapter 2 presents an analysis of Mycobacterium riyadhense from an evolutionary genomics point of view, followed by functional genomics experiments to look for clues obtained from the comparative genome analysis of M. riyadhense and other mycobacteria including members of the MTBC. The third chapter describes an imported case of Mycobacterium leprae found in Riyadh, Saudi Arabia, revealed by metagenomic sequencing and bioinformatic analysis, which was challenging for the clinicians to treat due to lack of timely diagnosis and occurrence of drug resistance during the course of treatment. The fourth chapter describes how applications of NGS facilitate rapid pathogen discovery in an imported case of Naegleria fowleri from the Cerebrospinal fluid (CSF) of a resident in KSA with recent travel history to Pakistan. The fifth chapter presents how we have monitored an ongoing outbreak by drug-resistant strains of the human pathogenic yeast Candida auris in Saudi Arabia from King Faisal Medical City, Riyadh, Saudi Arabia. In this thesis, I have shown several applications of NGS and bioinformatic analysis protocols in the clinical genomics/metagenomics fields. I believe some of the main clinical applications of NGS will lead to the adoption of these methodologies in clinical settings in Saudi Arabia in the forthcoming future.