Mental diseases, particularly mood and anxiety disorders, like major depression, general anxiety disorder, and bipolar disorder, are commonly diagnosed during the perinatal period and may represent a risk factor for the occurrence of several adverse events for the mother, the gestation, the fetus, and the newborn. To date, no randomized controlled double-blind clinical trials (RCTs) are allowed for ethical purpose, in the gestational period, so that only observational longitudinal studies, including case-control and cohort studies investigated the safety of psychotropic drugs (PDs) during pregnancy and/or breastfeeding. Many data concerning the risks of PDs have also been summarized through systematic reviews and meta-analytic investigations. Currently, the available information coming from such studies is overly well-established, with a number of PDs which can be considered relatively safe in early and late pregnancy as well as during breastfeeding. It has also been well documented that an untreated severe psychiatric illness can determine a greater risk for both the mother, the gestation, the fetus, and the newborn. A general approach and some relevant clinical recommendations focused on the prescription of PDs during pregnancy and breastfeeding are also provided, according to the recent international guidelines and to the expert opinions in the field of perinatal clinical psychopharmacology, by providing an updated clinical practice flowchart to clinicians and researchers working in the field of perinatal psychiatry.