B cell lymphoma and multiple myeloma (MM) are the most common hematological malignancies which benefit from therapeutic monoclonal antibodies (mAbs)-based immunotherapies. Despite significant improvement on patient outcome following the use of novel therapies for the past decades, curative treatment is unavailable for the majority of patients. For example, the 5-year survival of MM is currently less than 50%. In the 1980s, interferon-α was used as monotherapy in newly diagnosed or previously treated MM with an overall response rate of 15-20%. Noticeably, a small subset of patients who responded to long-term interferon-α further achieved sustained complete remission. Since 1990, interferon-α-containing regimens have been used as a central maintenance strategy for patients with MM. However, the systemic administration of interferon-α was ultimately limited by its pronounced toxicity. To address this, the selective mAb-mediated delivery of interferon-α has been developed to enhance specific killing of MM and B-cell malignant cells. As such, targeted interferon-α therapy may improve therapeutic window and sustain responses, while further overcoming suppressive microenvironment. This review aims to reinforce the role of interferon-α by consolidating our current understanding of targeting interferon-α with tumor-specific mAbs for B cell lymphoma and myeloma.