Metabolic syndrome (MetS) stands as the leading global cause of mortality, with extensive research highlighting its widespread prevalence in various African nations. This metabolic complex disorder is characterised by a cluster of interconnected factors that significantly increase the risk of developing cardiovascular diseases and type 2 diabetes mellitus. MetS is a complex disease with several components, including lifestyle, nutrition, comorbidities, and genetic inheritance. The genetic component is a crucial determinant of not only MetS susceptibility but also therapeutic response variability. Despite its complexity and prevalence, there are no well-defined treatments. The therapeutic strategy involves the independent treatment of each component. In this chapter, we aim to (a) emphasise the role of genetic variations in determining MetS susceptibility and (b) report genetic variants associated with drug response variability among North African populations. This chapter reveals that African populations exhibit significant genetic diversity in the pharmacogenetic factors, influencing their response to metabolic syndrome components. It highlights the intricate nature of genetic contributions to treatment outcomes, especially in admixed groups. Given the limited available data, there is a pressing need to conduct pharmacogenetic research within African populations to develop tailored guidelines that address their unique genetic characteristics, ensuring precise dosing and drug prescriptions while minimising the risk of severe adverse effects.