Digital therapeutics (DTx) for major depressive disorder (MDD) offer evidence-based, software-delivered interventions designed to expand therapy access and options. These interventions can function independently, such as stand-alone applications that may or may not include human guidance, or they can be combined in blended settings with pharmacological treatment or face-to-face treatment. This chapter explores DTx for MDD, covering their theoretical basis, scoping on Cognitive Behavioral Therapy, clinical efficacy, and factors influencing user acceptance and engagement, as well as current barriers related to implementation, such as insufficient training on DTx among health professionals, inconsistent frameworks, and national regulations of DTx. It also addresses adoption strategies, emphasizing the potential of blended care models for an optimized integration of DTx in therapeutic settings. Future directions, particularly the integration of wearables, artificial intelligence, and large language model chatbots for MDD relapse prevention, management, and treatment, are examined, highlighting their capacity to deliver personalized and accessible mental healthcare. Finally, the chapter delves into open questions concerning key challenges for developing human-centered and effective digital interventions for patients with MDD, such as changes in the role, quality, and form of digital therapeutic alliance.