"Handle with Care" is the first track from the Traveling Wilburys' 1988 album, Traveling Wilburys Vol. 1, and the group's most successful single. Writing credits are shared by all five band members, George Harrison, Jeff Lynne, Roy Orbison, Tom Petty, and Bob Dylan.

The single reached #45 on the Billboard Hot 100 chart, #2 on the Billboard Mainstream Rock Tracks chart, #21 on the UK singles chart and #3 on the ARIA Chart.

The song received a highly positive retrospective review from Allmusic journalist Matthew Greenwald, who described the song as "one of the most memorable records of the 1980s." Greenwald wrote: "Musically, the song is built around a descending, folk-rock chord pattern and some fine major-key chorus movements. George Harrison handles the verses, and there are also two excellent bridges featuring Roy Orbison and Bob Dylan. Orbison's section capitalizes on his awesome, operatic vocal pipes, and the effect is wonderful." The opening chords are reminiscent of Jeff Lynne's "10538 Overture", the ELO single from 1972.

The song was originally intended as the B-side of Harrison's "This Is Love". Harrison had not yet written a song for the B-side when an impromptu gathering of the musicians who became the Wilburys turned into an informal songwriting and jam session. Casting about for a song idea while relaxing in a garden near Bob Dylan's recording studio, Harrison was inspired when he noticed a box in Dylan's garage that was labelled "Handle with Care". The box also inspired the opening line: "been beat up and battered around." The complete song quickly followed, with different members of the gathering contributing various lines. The group moved to a recording studio and quickly laid down the basic tracks which were later polished by eventual Wilburys producer Jeff Lynne. The song depicts a conversation between a man and his new found love wherein he is recounting life's experiences which have affected him, contributed to his loneliness, and his plea to his love to "handle me with care" because of all the things he had been through.

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