Periprosthetic joint infection (PJI) after arthroplasty is a major complication, which requires significant resources, resulting in high costs for the medical system. In recent years, significant progress has been made in the diagnosis and treatment of periprosthetic infections, the identification of the pathogen being the central element in the establishment of targeted antibiotic therapy. Next-generation sequencing (NGS) or metagenomic NGS (mNGS) represents a promising, fast alternative, with increased specificity and sensitivity compared to identification methods using conventional culture media, thus enabling an increased rate of identification of pathogenic microorganisms and antibiotic resistance genes (ARG). The purpose of this article was to highlight new molecular diagnostic methods for periprosthetic joint infections and their involvement in treatment efficiency. NGS technologies are cutting-edge techniques that may challenge the PJI diagnostic model.