Ketamine is a racemic mixture of the enantiomers arketamine and esketamine whose rapid and sustained antidepressant effects and antisuicidal potential have raised considerable interest in psychiatry and neuropsychopharmacology. Esketamine was approved in 2019 in the USA, Canada, and Europe for the management of treatment-resistant depression. Bioinformatics methods, such as network pharmacology, and molecular docking, are useful for predicting new molecular targets and mechanisms of action of drugs with polypharmacological potential. Omics sciences have provided a wealth of information from public databases that have contributed to molecular target predictions. This chapter provides an overview of main and new molecular targets predicted by bioinformatics that may be involved in the antidepressant and antisuicidal effects of esketamine and arketamine. Based on our new integrated bioinformatics analysis for this textbook, the new molecular targets predicted are interleukin (IL)-6R and protein Janus kinases (JAK)1 and JAK2. These targets are associated with inflammatory processes and may be responsible for the worsening of depressive symptoms in patients refractory to conventional treatments. Further studies need to validate the clinical relevance of the predicted targets for the activity of ketamine.