Recent improvements in next-generation sequencing technologies have enabled clinical laboratories to increasingly pursue pathogen genomics for infectious disease diagnosis. Clinical laboratories can also benefit from whole-genome sequence characterization of cultured isolates, helping to resolve infection prevention questions pertaining to pathogen outbreaks and surveillance. Metagenomic sequencing from primary specimens can also provide laboratories with an unbiased universal test for situations where traditional methods fail to identify infectious etiologies despite, high clinical suspicion. Here, the most useful applications of whole-genome sequence and metagenomic sequencing are summarized, as are the main advantages, limitations, and considerations for building an in-house clinical genomics program.