Due to its universal applications, Polymerase Chain Reaction (PCR) became an essential technique in various scientific branches such as microbiology, biotechnology, oncology, clinical studies, forensic science, phylogenetic studies, migration studies, and genetic testing. It can selectively amplify a nucleotide sequence from a complex mixture of sequences with a reproducible and easily operatable protocols in a common laboratory. The modern PCR workflows and systems have advanced to a point where it can amplify a low abundant nucleotide sequence from a single cell and run high-throughput runs using nano well or chip-based systems. In this chapter we are taking a tour that explores the fundamentals of PCR and its components, mode of action of various PCR workflows and systems, foundation of primer designing, and optimizations of PCR protocols.