Cancer, an abnormal and uncontrolled cell division, has engulfed the lives of unlimited people till date. Etoposide and Teniposide are podophyllotoxin derivatives and have been used clinically for treatment of refractory testicular tumor and cancer. These compounds arrests cell growth by DNA topo II inhibition, which causes double strand breaks in DNA and known as non-interclating topo II inhibitors. They have many side effects, such as myelosuppression, poor water solubility, and the development of resistance so modification is done on it at various sites. Podophyllotoxin contains a five-ring system. Modification of the A-ring gave compounds having significant activity but less than that of Etoposide, whereas modification of the B-ring resulted in the loss of activity. E-ring is essential for its anticancer activity and D-ring in lactone form is preferred for better activity. The introduction of double bond in C-ring lowers the activity but modifications at the C-4 in C-ring with bulkier groups enhance anticancer activity. NK-611, GL-331 and Etoposide phosphate are water soluble derivatives of Etoposide with potent anticancer activity and are currently in clinical trials.