The Japanese Government says it plans to kill 260 whales - a substantial increase on last year's catch - in the name of scientific research.
The hunt comes weeks after Japan failed to get a commercial whaling ban lifted at a meeting of the International Whaling Commission (IWC).
Opponents say Japan's research programme is really commercial whaling in disguise, because the government sells the whale meat to restaurants and supermarkets to pay for the project.
In all, five vessels will hunt the whales in the north-west Pacific over the next three months.
The first ships left the south-west Japanese city of Shimonoseki on Friday and Saturday, and will be followed by a final ship on 14 July.
Endangered species
This year's hunt will include the sei species of whale, which has remained untouched for the past 26 years.
Japan's planned whale catch
150 minke
50 Bryde
50 sei
10 sperm
The United States lists the pointed-snout sei whale as endangered, but Japan says the species has swelled from 9,000 in 1978 to about 28,000.
"Sei whales are much larger than other whales, such as the minkes, and eat more fish," said Takanori Nagatomo of the Japanese Fisheries Agency.
"It is impossible to know their impact on the marine environment without knowing how much, and what, they eat," he said.
Japan blames the whales' huge consumption of fish for a 50% drop in fish catches over the past 20 years.
Washington has in the past threatened sanctions over the expansion of Japan's whaling programme, but Japan remains defiant, accusing its critics of hypocrisy and insisting there are enough stocks for a return to controlled commercial whaling.
Research disputed
Japan says its research programme is necessary to chart the whales' behaviour and diet.
The project costs about $37m a year and is partly financed by selling the whales' meat, which is considered a delicacy in Japan.
"Even though they call it research whaling, it's really commercial whaling," said Motoji Nagasawa, from Greenpeace in Japan.
"They have to expand it in order to keep the prices for whale meat down," he said.
Japan's research programme is permitted by the IWC, which banned commercial whaling in 1986 in order to protect endangered species.