Mokonyane went on to lead the ANC's internal organising department at Luthuli House until her election to the Deputy Secretary-General post at the party's 55th National Conference in December 2022.

[16] In October 2007, while Housing MEC, Mokonyane launched an unsuccessful campaign to succeed Mbhazima Shilowa as Provincial Chairperson of the ANC in Gauteng.

[21] The Sowetan reported that the Gauteng ANC was divided by factionalism, with opposing groups aligned respectively to Mokonyane, Mashatile, and leadership contender Angie Motshekga.

[32] In October 2013, Mokonyane was criticised for remarks she made on a visit to Bekkersdal, Gauteng, during violent service delivery protests in the town.

[34] In subsequent days, Mokonyane announced that the government would establish a multi-level task team to investigate allegations of corruption and improve administration in Bekkersdal.

[38] On 26 May 2014, pursuant to the general election, President Jacob Zuma appointed Mokonyane to his second cabinet as Minister of Water and Sanitation, a newly created ministry in the national government.

[5] City Press later described Mokonyane's tenure in the ministry as defined by "tremendous decline in investment in capital projects, the systematic destabilisation of water boards and the departure of key and senior personnel".

[41] Controversial decisions taken by Mokonyane included the R4-billion decision to delay Phase II of the Lesotho Highlands Water Project, which Mokonyane said was related to the need to ensure that the project served the imperative of economic transformation but which senior officials said was part of an attempt to ensure that related state contracts went to LTE Consulting, an ANC donor.

[44] On the day that Mokonyane vacated the portfolio in February 2018, the Standing Committee on Public Accounts (Scopa) and the Portfolio Committee on Water and Sanitation announced a full parliamentary inquiry into alleged maladministration and corruption at the Department of Water and Sanitation, which Scopa chairperson Themba Godi said had "ceased to function like a normal department" and had "effectively been destroyed".

[49][50] On 27 February 2018,[5] Mokonyane was appointed Minister of Communications in a reshuffle of the cabinet by newly elected President Cyril Ramaphosa, who took office after Zuma resigned.

Opposition parties, and the ANC's own ally the Congress of South African Trade Unions, responded by calling for Ramaphosa to drop Mokonyane from the cabinet entirely.

[53] Mokonyane was listed tenth on the ANC's party list during the national election, securing Mokonyane her first full term in a seat in the National Assembly,[37] and the ANC announced that Ramaphosa did not intend to reappoint her to cabinet but would instead nominate her to serve as a presiding officer in the assembly, as House Chairperson for Committees ("chair of chairs").

[55] She was appointed to a full-time role as the ANC's Head of Organising, in which capacity she helped introduce a new digital system for recording party membership.

[62] Other witnesses claimed that Bosasa had paid for a birthday party for Mokonyane, for her family's groceries, for security upgrades at her home, and possibly for her Aston Martin.

[6][65] The commission called her again in September 2020, after the owner of a guest house in Krugersdorp claimed that Mokonyane's 40th birthday party (in 2003) had been held at his property and had been financed by a R41,000 contribution from Bosasa.

[70] She accused the commission and its chairperson, Chief Justice Raymond Zondo, of meddling in politics, and announced that she intended to seek judicial review of the report.

[9] At the time he was a United Democratic Front activist and trade union organiser in Munsieville, Krugersdorp – indeed, he was arrested with Mokonyane shortly after their wedding in 1985.

[9] Their son, Retlabusa, died in November 2010 at the age of 23;[7] Lindiwe Sisulu controversially told the Mail & Guardian that he had killed himself after being "persecuted" by the media.