[17] While Penn was a first-year law student at Columbia University in 1976, he and his business partner Douglas Schoen became the pollsters for congressman Ed Koch's second run for mayor of New York City.

In 1977, with the campaign against Mario Cuomo for the Democratic nomination in full swing, Penn sought a way to conduct polls more quickly than the mainframe and punched card system he and Schoen were making use of at Columbia University.

[19] Penn also played a significant role in Koch's campaign during the 1985 New York City mayoral election, for which he and Schoen developed direct mailings,[20] set up phone banks, organized volunteers and canvassers, and coordinated fundraising.

That year, Koch won both the Democratic primary and the general election, defeating New York City Council President Carol Bellamy.

Since 1979, Penn's firm has helped elect more than a half dozen heads of state in Latin America, including Venezuela's Carlos Andrés Pérez,[23] Belisario Betancur and Virgilio Barco Vargas of Colombia, and Leonel Fernández of the Dominican Republic.

"[25] Penn & Schoen applied the rapid polling techniques they had developed on Ed Koch's first campaign for mayor to provide Begin with a daily understanding of attitudes of the Israeli electorate.

[19] In 1993, Penn, Schoen & Berland was engaged by AT&T's new advertising agency FCB to guide a response to the "Friends and Family" plan offered by MCI, a then-upstart competitor for AT&T's long-distance services.

To help AT&T understand how best to counter MCI's strongest messages, Penn created the "mall testing" methodology for competitive advertising research.

[9] Penn also created the famous "blue sweater" advertisement that featured Gates, which were intended to restore trust in the company amid the antitrust litigation.

[27] In 2006, a survey of global opinion leaders found that Microsoft was the world's most trusted company, an accomplishment which The Wall Street Journal partially attributed to Penn's advice.

[33][34] In May 2016, Penn told The Wall Street Journal that he wanted to create a "more digitally-focused advertising holding group, made up of companies which do not overlap in function," and offer a "fully-integrated solution across the continuum of marketing services.

[40] Penn, alongside Victor Ganzi, Josh Harris, James Tisch, and Thomas Peterffy, contributed to a $50 million investment fund in The Messenger, a news website that launched in May 2023.

[10] In 1994, President Bill Clinton hired Penn & Schoen to help his administration recover from the Democratic Party's dramatic losses during that year's midterm elections.

[45] Beginning in August 1995, at Clinton's request, Penn conducted numerous polls to understand what the political ramifications would be if the federal government were to shut down over disagreement between the legislative and executive branches over the budget.

[19] Penn tested many different scenarios for Clinton, and in each case the research showed that the American public would back the President and blame Republicans if the government shut down.

Ultimately, Speaker of the House Newt Gingrich and the Republican-controlled Congress bore much of the political fallout for the shutdown, vindicating Penn's polling.

[45] When allegations of Clinton's extramarital affair with Monica Lewinsky first surfaced in January 1998, Penn conducted polls to help the administration craft its response.

[46] According to New York Times columnist Frank Rich, Penn and his wife, Nancy Jacobson, "helped brand the Hillary Clinton presidential campaign as a depository for special-interest contributions.

"[50] An NPR interview notes how much greater Mark Penn's business conflicts of interest were in comparison to other recent top campaign advisors like David Axelrod and Karl Rove.

[10] Penn advised Clinton not to apologize for voting for the Iraq War, insisting that "It's important for all Democrats to keep the word 'mistake' firmly on the Republicans.

Senior Clinton staffer Harold Ickes is reported to have asked in frustration, "How can it possibly be that the much vaunted chief strategist doesn't understand proportional allocation?

[52] Penn advised British prime minister Tony Blair and conducted polling during his successful campaign for an unprecedented (for a Labour Party leader) third term in 2005.

Penn's 2009 book, Microtrends, written with Kinney Zalesne and published by Hachette, argues that small groups of people can trigger big changes.

Penn argues that a mere one percent of the American public (3 million people) can create a "microtrend" capable of launching a major business or even a new cultural movement, changing commercial, political and social landscapes.

[70] During this period, CNN and MSNBC declined to book Penn and his frequent appearances on Fox were criticized by some interviewed by Politico who said he was seeking revenge against Democrats for saddling him with Hillary Clinton's defeat in the 2008 U.S. presidential election.

[72] Penn has used the term "deep state" to refer to what he characterizes as Democratic operatives within the government who seek to undermine and sabotage Trump's first presidency.

[76] In an April 2023 op-ed, Penn outlined a path to victory for a presidential candidate to win through appeals to an educated, suburban base[77] and expressed hope for Governor of Florida Ron DeSantis, citing, among other things, a motivation to prevent Trump from becoming president again.

[78] Penn is married to Nancy Jacobson, the co-founder, board president and CEO of No Labels, a 501(c)4 political organization that publicly claims to advocate for centrism and bipartisanship.