Rare diseases pose great challenges to clinical diagnosis due to their low incidence rate, diverse disease types, and complex mechanisms. Genetic factors account for approximately 80% of the causes of rare diseases. Therefore, genetic testing is a crucial tool for etiological diagnosis of rear diseases. In recent years, exome sequencing has gradually become a frontline detection technology for clarify the genetic causes of rare diseases. It has significantly improved the diagnostic rate of patients with rare diseases. This article provides an overview of the development of genetic testing technologies for rare diseases and explores potential nextstep testing strategies for cases that remain undiagnosed after exome sequencing. The nextstep testing strategies include sequencing techniques such as whole genome sequencing and longread sequencing, which have more advantages in coverage and detections of variant types. Some auxiliary testing methods such as transcriptomics, epigenetics, proteomics, and metabolomics analysis should be also included. We also evaluate the advantages and the limitations of each technology in the discovery and interpretation of genetic variations in rare diseases. Furthermore, we summarize the establishment and utilization of existing rare disease databases in different countries. We also discuss the importance of automated reanalysis of genomic data based on databases to identify patients with similar phenotypes or genetic mutations. All in all, aims of this article are to provide clinicians and researchers with alternative genetic testing strategies and technology options when exome sequencing fails to provide a diagnosis