Molewa became the Minister of Water and Environmental Affairs of South Africa on 31 October 2010, as part of a cabinet reshuffle by President Jacob Zuma.

[2] In 1994 Molewa became the first female Chairperson of the Portfolio Committee on Trade and Industry, and in 1996 went on to serve as a member of the Executive Council on Tourism, Environment and Conservation.

[4] On 30 April 2004, she became the first woman Premier of the North West Provincial Government, a post she held until 2009, and is credited with having put the province on a successful track.

[2] From the time Molewa assumed her role as Minister of Environmental Affairs she worked to advance the integrated strategic management of rhinoceroses through a variety of conservation-minded efforts approved by the president's cabinet.

[14][15][16] Molewa also announced that a 22-member commission would decide whether to propose the international sale of the South African government's 21 metric ton rhino horn stockpile.

[34] The proposal and subsequent approval, signed off in June 2017 while it was supposedly still under scientific scrutiny, has evoked major criticism by, and concern among, local and international conservationists, scientists, animal welfare organizations and the public, for the impact this will have on the conservation of lions and big cats worldwide and for the ethical implications this has for the industry, which is considered highly unregulated and cruel.

[34] The shift in the market towards countries listed by global conservation and law enforcement agencies as having weak regulation and high corruption levels has been flagged as a major concern since it provides many opportunities for intensive illegal trade in wild animals.

[38] Quotas have been declared since 2017 in accordance with the advice provided by the Scientific Authority (SA)[39] on principles of demand and supply[34] and with the results of the South African National Biodiversity Institute's (SANBI) three-year research project, started in 2017 and still underway.

[34] A growing global awareness around the consequences of being linked to this contentious industry and the criticism it draws, led the largest lion bone carrier, Singapore Airlines, to decide to stop transporting big cat body parts from South Africa, beginning in August 2018.

[40][41] In February 2013, while Minister of Water Affairs, Molewa awarded a R419 million IT contract to Business Connexion instead of using the State Information Technology Agency.

As a result, the suspended director general continued to receive a paycheck for roughly two years while fighting charges that were eventually dropped by the new Minister of Water and Sanitation.