Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes resulting from genetic defects transmitted in an autosomal dominant fashion, leading to β-cell dysfunction. Due to the lack of homogeneous clinical features and univocal diagnostic criteria, MODY is easily misdiagnosed as type 1 (T1DM) or type 2 (T2DM) diabetes mellitus, hence its diagnosis relies mostly on genetic testing. Fourteen subtypes of MODY have been described to date, of which MODY12 is caused by diverse mutations affecting the adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene, involved in the regulation of insulin secretion from β-cells. The complexity of MODY12 genetic picture is mirrored by a variety of clinical manifestations, encompassing a wide spectrum of disease severity. Although well-established, the inconsistency of genotype-phenotype correlation has not been fully understood. A correct diagnosis is crucial for the choice of adequate treatment and outcome improvement. Directly targeting the defective gene product, sulfonylureas are the preferred medications in MODY12, although treatment efficacy may vary according to the genotype. Here, we provide a comprehensive review of MODY12 pathophysiology, genetic and clinical features, and current therapeutic options. We also illustrate three case reports in whom a diagnosis of MODY12 was suspected after the identification of novel ABCC8 variants that turned out to be of unknown significance We discuss that careful interpretation of genetic testing is needed even on the background of a suggestive clinical context. Our findings highlight the need for further research to unravel MODY12 disease mechanisms, as well as to clarify the pathogenicity of identified ABCC8 variants and their influence on clinical presentation and response to therapy.