Second-generation antipsychotics (SGAs) are among the most prescribed psychotropic drugs worldwide. Nevertheless, their adverse effect profiles are notoriously broad and often pose clear challenges for tolerability, adherence, quality of life, and overall clinical success in everyday practice. Most alarmingly, a relationship has been described between SGAs and several metabolic disturbances, ultimately increasing the risk of metabolic syndrome, cardiovascular disease (CVD), diabetes, and other related conditions. However, characterizing this link is complex, as the impact of SGAs appears to be highly variable, not only based on clinical outcomes, but also in regards to a myriad of other patient-dependent factors, such as their age, sex, diagnosis, comorbidities and concurrent medication use. Appraisal of this interplay is pressing as CVD remains the leading global cause of morbidity and mortality. The outlook is further complicated by the intrinsically higher cardiometabolic risk entailed by severe mental illnesses such as schizophrenia—the model psychotic disorder—and other mental disorders where SGAs are often prescribed. Therefore, the objective of this narrative review is to revise the currently available clinical evidence on the relationships between SGAs and weight gain, hyperglycemia, dyslipidemia, hypertension, systemic inflammation, thrombotic risk and cardiovascular risk; in an effort to illuminate directions for clinical practice and future research.