He described himself as one of the seven founders of Hamas and was considered by many as second only in importance to the group's crippled spiritual leader, Shaikh Ahmad Yasin.
Yasin was assassinated in a similar missile attack by Israel in March.
A paediatrician by training, Dr al-Rantisi was a popular figure in Gaza and defended any and all means that would force Israeli troops and illegal settlers to leave Palestine.
A committed Islamist, al-Rantisi rose to prominence with Hamas during the first Palestinian Intifada in the late 1980s and early 1990s.
He was arrested by Israel several times, spending as much as two and a half years in prison on one occasion.
In late 1992, the doctor was among more than 400 Palestinians deported to Lebanon.
He became a spokesman for the deportees in his camp, Marj al-Zahur.
After his return to Gaza, he proved no more popular with Yasir Arafat's Palestinian Authority than he had been with the Israeli government.
Palestinian officials arrested him in 1998 after he demanded that a number of senior PA figures should resign.
The Palestinian High Court of Justice ordered his release two months after he was arrested.
Damascus-based Khalid Mishaal
now most senior Hamas figure
He remained a regular critic of the PA, condemning it for its apparent willingness to compromise with Israel as part of the road map peace plan.
Al-Rantisi criticised Prime Minister Mahmud Abbas for participating in a conference with Israeli Prime Minister Ariel Sharon and US President George Bush in Jordan in June 2003.
In 2003, al-Rantisi survived an Israeli assassination attempt.
Suffering leg, arm and chest wounds, the spokesman escaped a US-made Apache helicopter gunship attack.
The helicopter fired seven missiles on his car, and killed two passersby - a mother and her five-year-old daughter.
His death leaves Khalid Mishaal - Hamas' politburo chief living in exile – as the most senior and best-known representative for the Islamist resistance movement.