Cancer is one of the diseases with high morbidity and mortality on a global scale. Chemotherapy remains the primary treatment option for most cancer patients, including patients with progressive, metastatic, and recurrent diseases. To date, hundreds of chemotherapy drugs are used to treat various cancers, however, the anti-cancer efficacy and outcomes are largely hampered by chemotherapy-associated toxicity and acquired therapeutic resistance. The natural product (NP) oridonin has been extensively studied for its anti-cancer efficacy. More recently, oridonin has been shown to overcome drug resistance through multiple mechanisms, with yet-to-be-defined bona fide targets. Hundreds of oridonin derivative analogs (oridonalogs) have been synthesized and screened for improved potency, bioavailability, and other drug properties. Particularly, many of these oridonalogs have been tested against oridonin for tumor growth inhibition, potential for overcoming therapeutic resistance, and immunity modulation. This concise review seeks to summarize the advances in this field in light of identifying clinical-trial level drug candidates with the promise for treating progressive cancers and reversing chemoresistance.