[2] In 2000 it relocated to a former spice milling factory in Dumbo, Brooklyn,[2] where it has served as a stage for musicians such as David Bowie, Lou Reed, Joe Strummer, Aimee Mann, Nick Cave, Rufus Wainwright and John Cale.

In addition, the organization raised approximately $4 million for the building's restoration, including its historic stained glass windows by William Jay Bolton, which were the first made in America.

From its inception, St. Ann's has earned a reputation as a consistent innovator, forging multi-disciplinary theatrical collaborations, thematic multi-artist concert presentations, and new works for puppet theater.

The seven-year cantata series proved instrumental in forming St. Ann's genre-defying approach to music programming and helped build the reputation of The Orchestra of St. Luke's, then a new band.

The Seven Deadly Sins lead to the sextet, Hudson Shad, and the award-winning production of Susan Feldman's In the Time of the Comedian Harmonists (1992), which went on to enjoy a long life as Band in Berlin, co-directed by Pat Birch, Associate Director and Choreographer Jonathan Cerullo, including a brief stint on Broadway in 1999.

This was followed by several Halloween programs, including Nevermore: Readings from Edgar Allan Poe and the Harry Smith Project in 1999, which featured Nick Cave, Van Dyke Parks, Rufus Wainright, Thurston Moore, and others.

Other events that took place in the old building were St. Ann's commissions of Bill Frisell Plays For Buster Keaton (1992–1993), scores for six of the master's silent films; August Wilson & the Blues (1996), which brought together the Pulitzer Prize-winning playwright with the musician Olu Dara, and David Greenberger's The Duplex Planet Radio Hour, produced for WNYC-FM in 1994.

(2003), House/Lights (2005), The Emperor Jones (2006) and Hamlet (2007), Ridge Theater's Jennie Richee (2003), Decasia (2004); Joe Strummer's final New York appearances (2002), David Bowie (2002), Aimee Mann (2004), as well as intimate concerts with Laurie Anderson and Lou Reed (2002), Oscar Wilde's Salome: The Reading (2002) with Al Pacino, directed by Estelle Parsons, and the 20th anniversary production of Amy Trompetter's puppet opera, The Barber of Seville (May 2003), conducted by Kristjan Järvi with the Absolute Ensemble.

St. Ann's celebrated its 25th anniversary with a new presentation of Roy Nathanson's Fire at Keaton's Bar & Grill, featuring Deborah Harry, Lou Reed, Laurie Anderson, Antony, Chocolate Genius, Nellie McKay, Theo Bleckmann, Dan Zanes, and others.

In 2006/2007, St. Ann's produced two World Premieres: Lou Reed's Berlin, directed by Julian Schnabel, which traveled to the Sydney Festival, Australia and subsequently toured 14 European cities in summer 2007; and Part 2 of Cynthia Hopkins' Accidental Trilogy, Must Don't Whip 'Um.

The season ended with Hal Willner's Rogues Gallery Live, a gala benefit concert, featuring Bryan Ferry, Gavin Friday, Lou Reed, Laurie Anderson, Janine Nichols, Jennie Muldaur, Kembra, Baby Gramps, Antony, and others.

It has become an artistic home to such theater makers as Enda Walsh ("The Walworth Farce", "Penelope", "Misterman" with Cillian Murphy); John Tiffany and Steven Hoggett (the acclaimed "Black Watch" and "Let the Right One In"), director Emma Rice ("Brief Encounter", "Tristan & Yseult") and Grzegorz Jarzyna, whose outdoor "Macbeth" was staged in a former Tobacco Warehouse on the waterfront.

Throughout its existence, St. Ann's has presented a wide variety of concerts, including rock, jazz, world and roots music especially, and using its rising reputation to introduce new and overlooked artists to growing audiences.

Rare performances by Terry Allen, Michael Ventura and Butch Hancock, John Cale and Bob Neuwirth, Jeff Buckley and Mary Margaret O'Hara also took place, as well as St. Ann's production of David Byrne's orchestral music for "The Forest" at Town Hall in 1992.