An Electro-Static Discharge (ESD) protection device is formed in an isolated region of a semiconductor substrate. The ESD protection device may be in the form of a MOS or bipolar transistor or a diode. The isolation structure may include a deep implanted floor layer and one or more implanted wells that laterally surround the isolated region. The isolation structure and ESD protection devices are fabricated using a modular process that includes virtually no thermal processing. Since the ESD device is isolated, two or more ESD devices may be electrically “stacked” on one another such that the trigger voltages of the devices are added together to achieve a higher effective trigger voltage.