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The recognition of cardiovascular disease (CVD) as a “male” privilege has been a commonly held concept. However, emerging data describe another reality. Heterogeneities have been convincingly demonstrated regarding CVD manifestations, risk factor burden, and prognosis between males and females. The aim of the present narrative review was to highlight sex- and gender-related discrepancies in primary and secondary CVD prevention, underscoring plausible underlying mechanisms. Manifestation of CVD in women is characterized by atypical symptoms/signs and inadequately studied pathophysiology features challenging accurate diagnosis and effective treatment. Regarding CVD risk assessment, the burden and effect size of conventional, novel, and female-specific risk factors needs better clarification. Hitherto outcomes are nonconsistent, while most importantly, the interpretation of the attendant metabolic paths remains a challenge; the interactions among genetic, metabolic, and environmental factors are of high complexity regulated by genomic and nongenomic sex hormones effects. To deal with these key points, the National Institutes of Health currently calls upon investigators to provide a sex- and gender-specific reporting in all health research hypotheses. The implementation of high-quality studies addressing these issues is an imperative need to maximize cost-effectiveness in prevention and management strategies.