Klepfisz was born in the Warsaw Ghetto on April 17, 1941 and was 2 years old during the "varshever geto oyfshtand", (Yiddish for 'the Warsaw ghetto uprising'). Her father, Micha? Klepfisz, a member of "der algemeynernyidisher arbeter bund", (the Jewish Labour Bund), was killed on the second day of uprising.

Klepfisz escaped with her mother to the Polish countryside where they survived the Second World War by hiding and concealing their Jewish identities, aided by Polish peasants. After the war, the remaining family moved briefly to ?ód? before moving to Sweden in 1946. Irena and her mother moved to the United States in 1949.

Klepfisz attended City College of New York, and studied with distinguished Yiddish linguist Max Weinreich, a founder of the YIVO Institute for Jewish Research. Klepfisz graduated CCNY with honors in English and Yiddish.

In 1963, she attended the University of Chicago to do graduate work in English Literature. Irena Klepfisz received a Ph.D. in English in 1970.

She currently teaches at Barnard College

Today Klepfisz is respected as a Yiddishist, but her (mame-loshn, literally "mother tongue") was Polish; as a child she also learned Swedish. She began to learn Yiddish in Lodz in elementary school after the Second World War. She learned English after emigrating to the United States. In The Tribe of Dina: A Jewish Women's Anthology, which she co-edited with Melanie Kaye/Kantrowitz, Klepfisz describes the experience, up to age 16 or 17, of having "no language in which I was completely rooted.

Irena is well-known for her translations of Yiddish poets Kadya Molodowsky, and Fradl Shtok

Klepfisz has worked as an activist in feminist, lesbian, and secular Jewish communities. She is also co-founder of The Jewish Women's Committee to End the Occupation of the West Bank and Gaza (JWCEO). Along with Nancy Bereano, Evelyn T. Beck, Bernice Mennis, Adrienne Rich, and Melanie Kaye/Kantrowitz, Irena Klepfisz was a member of Di Vilde Chayes (English: The Wild Beasts), A Jewish feminist group that examined and responded to political issues in the Middle East, as well as to antisemitism.

Klepfisz began publishing her poems in 1971. She was a founding editor of Conditions , a feminist magazine emphasizing the writing of lesbians, and also was the co-editor of The Tribe of Dina: A Jewish Women's Anthology. She has also been a contributor to the Jewish feminist magazine Bridges

Irena Klepfisz has taught English, Yiddish, and Women's Studies.