Genomic studies have shown that large numbers of candidate targets are observed in breast cancer. Nevertheless, only a few of them are validated as relevant targets in clinical studies. Estrogen receptor (ER) and HER2 expressions could be associated with a level I evidence. Beyond ER and HER2, BRCA and PIK3CA mutations (when targeted with alpha-specific PI3K inhibitors) could be considered as promising targets in breast cancer since they have been associated with objective responses in phase I/II trials. In addition to these four molecular alterations, several others have shown promising results in preclinical studies and are being investigated in clinical trials. These genomic alterations include AKT1, ERBB2, and ESR1 mutations. These considerations highlight the lack of evidence for using multiplex technologies to individualize therapy in metastatic breast cancer. Sequencing multiple genes to treat metastatic breast cancer is very promising but should be done in the context of clinical trials, either to enrich phase I/II trials in patients with genomic alterations or to show medical usefulness of new biotechnologies like next-generation sequencing (NGS). Although most current approaches of precision medicine are aiming at targeting drivers, additional applications could be developed in the future. This includes the identification of DNA repair deficiencies, mechanisms of immune suppression, and identification of minority lethal subclones. Finally, one of the very promising applications of genomics for metastatic breast cancer is the identification of pathway activation or defects at the individual level. For example, gene expression and single nucleotide polymorphisms (SNP) signatures are being developed to detect kinase (such as mammalian target of rapamycin [mTOR]/CDK4) activations or DNA repair deficiencies.