The Indus River provides key water resources for Pakistan's economy – especially the breadbasket of Punjab province, which accounts for most of the nation's agricultural production, and Sindh. The word Punjab means "land of five rivers" and the five rivers are Jhelum, Chenab, Ravi, Beas and Sutlej, all of which finally flow into the Indus. The Indus also supports many heavy industries and provides the main supply of potable water in Pakistan.

The total length of the river varies in different sources. The length used in this article is 3,180 km (1,980 mi), taken from the Himalayan Climate and Water Atlas (2015). Historically, the 1909 The Imperial Gazetteer of India gave it as "just over 1,800 miles". A shorter figure of 2,880 km (1,790 mi) has been widely used in modern sources, as has the one of 3,180 km (1,980 mi). The modern Encyclopedia Britannica was originally published in 1999 with the shorter measurement, but was updated in 2015 to use the longer measurement. Both lengths are commonly found in modern publications; in some cases, both measurements can be found within the same work. An extended figure of circa 3,600 km (2,200 mi) was announced by a Chinese research group in 2011, based on a comprehensive remeasurement from satellite imagery, and a ground expedition to identify an alternative source point, but detailed analysis has not yet been published.

The ultimate source of the Indus is in Tibet, but there is some debate about the exact source. The traditional source of the river is the Sênggê Kanbab (Sênggê Zangbo) or "Lion's Mouth", a perennial spring not far from the sacred Mount Kailash, marked by a long low line of Tibetan chortens. There are several other tributaries nearby, which may form a longer stream than Sênggê Kanbab, but unlike the Sênggê Kanbab, are all dependent on snowmelt. The Zanskar River, which flows into the Indus in Ladakh, has a greater volume of water than the Indus itself before that point. An alternative reckoning begins the river around 300 km further upstream, at the confluence of the Sênggê Zangbo and Gar Tsangpo rivers, which drain the Nganglong Kangri and Gangdise Shan (Gang Rinpoche, Mt. Kailash) mountain ranges. The 2011 remeasurement suggested the source was a small lake northeast of Mount Kailash, rather than either of the two points previously used.

The Indus then flows northwest through Ladakh (Indian-administered Kashmir) and Baltistan and Gilgit (Pakistan-administered Kashmir), just south of the Karakoram range. The Shyok, Shigar and Gilgit rivers carry glacial waters into the main river. It gradually bends to the south and descends into the Punjab plains at Kalabagh, Pakistan. The Indus passes gigantic gorges 4,500–5,200 metres (15,000–17,000 ft) deep near the

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The major cities of the Indus Valley Civilisation, such as Harappa and Mohenjo-daro, date back to around 3300 BC, and represent some of the largest human habitations of the ancient world. The Indus Valley Civilisation extended from across northeast Afghanistan to Pakistan and northwest India, with an upward reach from east of the Jhelum River to Ropar on the upper Sutlej. The coastal settlements extended from Sutkagan Dor at the Pakistan-Iran border to Kutch in modern Gujarat, India. There is an Indus site on the Amu Darya at Shortughai in northern Afghanistan, and the Indus site Alamgirpur at the Hindon River is located only 28 km (17 mi) from Delhi. As of now, over 1,052 cities and settlements have been found, mainly in the general region of the Ghaggar-Hakra River and its tributaries. Among the settlements were the major urban centres of Harappa and Mohenjo-daro, as well as Lothal, Dholavira, Ganeriwala, and Rakhigarhi. Only 40 Indus Valley sites have been discovered on the Indus and its tributaries. However, it is notable that majority of the Indus script seals and inscribed objects discovered were found at sites along the Indus river.

Most scholars believe that settlements of Gandhara grave culture of the early Indo-Aryans flourished in Gandhara from 1700 BC to 600 BC, when Mohenjo-daro and Harappa had already been abandoned.

The Rigveda describes several rivers, including one named "Sindhu". The Rigvedic "Sindhu" is thought to be the present-day Indus River. It is attested 176 times in its text, 94 times in the plural, and most often used in the generic sense of "river". In the Rigveda, notably in the later hymns, the meaning of the word is narrowed to refer to the Indus river in particular; for example, in the list of rivers mentioned in the hymn of Nadistuti sukta. The Rigvedic hymns apply a feminine gender to all the rivers mentioned therein, except for the Brahmaputra.

The word "India" is derived from the Indus River. In ancient times, "India" initially referred to those regions immediately along the east bank of the Indus, where are Punjab and Sindh now but by 300 BC, Greek writers including Herodotus and Megasthenes were applying the term to the entire subcontinent that extends much farther eastward.

The lower basin of the Indus forms a natural boundary between the Iranian Plateau and the Indian subcontinent; this region embraces all or parts of the Pakistani provinces Balochistan, Khyber Pakhtunkhwa, Punjab and Sindh and the countries Afghanistan and India. The first West Eurasian empire to annex the Indus Valley was the Persian Empire, during the reign of Darius the Great. During his reign, the Greek explorer Scylax …

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• Gar River
• Gilgit River
• Gomal River
• Haro River
• Hunza River
• Kabul River
• Kunar River
• Kurram River
• Panjnad River
• Shyok River
• Soan River
• Dras River (or Shingo River)
• Swat River
• Zanskar River
• Luni river
• Zhob River