Objectives The Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD) is a consensus-based medication guideline. To reflect advances in pharmacotherapy for depressive disorders, we have undertaken a fourth revision of the KMAP-DD. Methods The review committee for the new version of the KMAP-DD (KMAP-DD 2021) included 143 Korean psychiatrists with clinical experience in the field of depressive disorders. Each treatment strategy or treatment option was evaluated with an overall score of nine, and the treatment option was categorized into the three levels of recommendation of primary, secondary, and tertiary. Results The first-line pharmacotherapeutic strategy for mild to moderate major depressive episodes (MDE) was antidepressant (AD) monotherapy. For severe MDE without psychotic features, AD monotherapy or the combination of AD and atypical antipsychotics (AAP) was the first-line strategy. The combination of AD and AAP was recommended as the first-line for the MDE with psychotic features as well. When treatment response to initial AD monotherapy was insufficient, a combination of AAP or another AD was recommended. In the case of unsatisfactory response to initial treatment with an AD and AAP combination, switching to another AAP or adding another AD was recommended. Conclusion Generally, there were no significant changes in the recommendations for MDE management in the KMAP-DD 2021 compared to previous versions. However, it was notable that the preference for the use of AAP and AD with the novel mechanism of action including vortioxetine and agomelatine increased.