Australia's army couldn't stop the cane toads, which number around 200 million. Residents swinging golf clubs failed and so did a campaign to freeze them to death in refrigerators.
But now an Australian scientist says evolution has seen the biggest and fastest cane toads interbreed, resulting in arthritis and bad backs which could slow them down.
"Cane toads moving across Australia are the fastest amphibians on Earth after their rapid evolution from slow-moving homebodies into road warriors over the past 70 years," Rick Shine at Sydney University said.
Thousands of cane toads moving in a front across tropical eastern Queensland state can travel 10 metres (30 feet) overnight, researchers say.
Those at the front of the invasion near the Western Australian state border can cover one km on a wet night – 10 times the distance.
"Toads that run at the front of the pack are becoming bigger and faster. They have different personalities, different shapes and are developing different physiologies," said Mr Shine.
The bigger, faster toads produce babies with bigger front legs and longer backs and consequently suffer arthritis.
"We are seeing toads in the Northern Territory with spinal arthritis – big, bony lumps on their spine," said Mr Shine.
Cane toads are one of Australia's worst environmental mistakes, ranking alongside the catastrophic introduction of rabbits.
The toads, introduced in a batch of 101 from Hawaii in 1935 in a failed bid to control native cane beetles, have spread 3,000km (1,900 miles) from northeast Queensland to Darwin in Australia's tropical north.
The spread of the toads, whose skin is poisonous, has led to dramatic declines in populations of native snakes, goanna lizards and quolls, a cat-sized marsupial.