He began his career on-stage in New York, in numerous Off-Broadway and Broadway plays including Peter Shaffer's Amadeus, John Patrick Shanley's Italian American Reconciliation, and Brian Friel's Aristocrats.
After a starring role in William Friedkin's To Live and Die in L.A., he began appearing regularly in film and on television, playing Ira Buchman for all eight seasons of Mad About You and later Merc Lapidus on Episodes.
While visiting a friend in New York City, Pankow auditioned for, and won, a role in an episode of PBS' Great Performances entitled "Life on the Mississippi".
He went on to perform in several Off-Broadway productions including Aristocrats, Italian American Reconciliation, and the New York Shakespeare Festival's The Tempest, Two Gentlemen of Verona and Henry VIII.
He subsequently appeared for eight seasons as Ira Buchman on the NBC sitcom Mad About You, where he was nominated for four Screen Actors Guild Awards for Outstanding Performance by an Ensemble in a Comedy Series.