Full-length CD33 (CD33FL) is a sialic acid-binding immunoglobulin-type lectin (Siglec) that is found on maturing and mature myeloid cells as well as on neoplastic cell counterparts. With this, CD33FL has long been an attractive therapeutic target. Most work to date has focused on immunotherapy of acute myeloid leukemia (AML) because CD33FL is displayed on at least a subset of the leukemic blasts in almost all cases and possibly underlying leukemia stem cells in some. Benefit in some patients treated with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates CD33FL as AML drug target. More recently, interest has arisen in therapeutically targeting splice variants of CD33 that lack the extracellular domain recognized by most current CD33 antibodies, including GO. Expanding the use beyond AML, there is increasing interest in targeting CD33 for other malignant and non-malignant disorders. These efforts comprise the targeting of CD33+ tumor cells in other malignancies (e.g. myeloid neoplasms other than AML, plasma cell disorders), CD33+ myeloid-derived suppressor cells (to overcome immune-suppressive microenvironments in a variety of cancers and non-malignant diseases), and normal CD33+ microglial cells (e.g. to treat Alzheimer disease). Early clinical result in the next 2-5 years may clarify the validity of such strategies.