All trans-retinoic acid (ATRA) as well as several key retinoids including tamibarotene, acyclic retinoid (ACR), and WYC-209, have made a major progress in both pre-clinical cancer therapeutics as well as in the clinical setting regarding the treatment of leukemia and solid tumors via their important impacts on cancer stem cell differentiation or apoptosis. ATRA exerts its antitumor activity by binding to retinoic acid receptors, which in turn specifically bind to DNA as a heterodimer with the retinoid X receptors, at promoter regions known as retinoic acid response elements. The impressive new studies and clinical achievements with retinoids as key pre-clinical research tools and antitumor agents, are summarized and discussed in the current paper. The ongoing clinical trial of tamibarotene, which is the first agent targeting super-enhancers-containing cancers, could provide a new treatment modality for acute myeloid leukemia patients. A recent clinical study for evaluation of the preventive effects of ACR on second primary hepatocellular carcinoma (HCC) demonstrated that the oral administration of ACR for 12 months, significantly reduced HCC recurrence. WYC-209 strongly inhibited cell proliferation of different tumor repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, and also blocked > 80% of B16 TRCs' lung metastases in wild-type C57BL/6 mice, without any apparent toxicity. These remarkable findings reveal that retinoids constitute a promising class of antitumor agents for the treatment of both hematological malignancies and solid tumors.