Previous guidelines for the treatment of people with type 2 diabetes mellitus (T2D) have relied heavily upon rigid algorithms for the sequential addition of pharmacotherapies to achieve target glycemic control. More recent guidelines advocate a personalized approach for diabetes treatment, to improve patient satisfaction, quality of life, medication adherence and overall health outcomes. Clinicians should work with patients to develop personalized goals for their treatment, including targeted glycemic control, weight management, prevention and treatment of associated comorbidities and avoidance of complications such as hypoglycemia. Factors that affect the intensity of treatment and choice of pharmacotherapy should include medical and patient influences. Medical considerations include the diabetes phenotype, biomarkers including genetic tests, and the presence of comorbidities such as cardiovascular, renal, or hepatic disease. Patient factors include their treatment preference, age and life expectancy, diabetes duration, hypoglycemia fear and unawareness, psychological and social circumstances. The use of a personalized approach in the management of people with T2D can reduce the cost and failure associated with the algorithmic "one-size-fits-all" approach, to anticipate disease progression, improve the response to diabetes pharmacotherapy and reduce the incidence of diabetes-associated complications. Ultimately, the use of personalized medicine in people with T2D should improve medication adherence, patient satisfaction and quality of life to reduce diabetes distress and improve physical health outcomes.