Gravitating toward the reformist side of the political spectrum (even though his father had been one of the pillars of the Old Regime), in 1941 he founded along with Víctor Paz Estenssoro and others, the influential Revolutionary Nationalist Movement (Movimiento Nacionalista Revolucionario, or MNR).

However, he is soon arrested for continuing agitation against the government in power and sent to the island prison of Isla de la Luna (Coati) on lake Titicaca.

[2] In October 9, 1949, he returns clandestinely to Bolivia and appears in the Bolivian congress at his assigned bench demanding his back pay--this public relations coup cements his image as a leader of the resistance against a tyrannical government.

However, the ultra-conservative government of Mamerto Urriolagoitía refused to recognize the results and instead turned over the presidency to the commander of the Bolivian army, general Hugo Ballivián.

At that point the MNR party went underground and on 9–11 April 1952 led the historic Bolivian National Revolution, aided by defections from the armed forces to the rebel cause (key among which was general Antonio Seleme).

Siles played a major role in the revolutionary uprising, along with Juan Lechín, since the MNR leader Paz Estenssoro was at the time in exile in Argentina.

The economy was in deep trouble, as food and mineral production had plummeted; consequently, inflation soared, and the United States conditioned any further aid and support on the adoption of an economic program of its own prescription (the so-called Eder plan) in late 1956.

Siles also had to tackle the difficult issue of disarming the worker and miner militia members who had fought in the 1952 Revolution and who had been allowed to keep their weapons.

Siles initially supported the November 1964 coup d'état by vice-president, General René Barrientos and army chief Alfredo Ovando — but was later exiled when it became apparent that the military intended to manipulate 1966 electoral results to perpetuate itself in power.

In 1971 Siles formed the Leftwing Revolutionary Nationalist Movement (Movimiento Nacionalista Revolucionario de Izquierda, MNRI), beginning a steady leftwards drift.

Days before Congress was due to convene to choose a winner, the army launched the bloody coup of 17 July 1980, which installed a reactionary (and cocaine-tainted) dictatorship of General Luis García Meza.

The unions, led by their old leader Juan Lechín, paralyzed the government with constant strikes, and even the vice-president, Jaime Paz, deserted the sinking ship when Siles' popularity sank to an all-time low.

[5] One bright point in the Siles administration was the 1983 extradition to France of the Nazi war criminal Klaus Barbie, known as the Butcher of Lyon.

His old rival, MNR's Víctor Paz Estenssoro was elected president, and Siles left for Uruguay, a country where he had lived before in exile and for which he held special affection.