Never Let Me Go is saturated in a mood of melancholic sadness. Kathy H. and her two close friends Tommy and Ruth know their lives will be fleeting and filled with pain at the end. They are clones, born only to be harvested as body parts to save the lives of other people when they enter their twenties or early thirties. They are not considered fully human, even though they are.

Because of the inevitability of pain and early death as well as the narrow confines of their lives, a bittersweet mood overhangs everything that happens to them. They never once leave the confines of their boarding school until they are sixteen, giving everything that occurs there a heightened importance. In the two years they have between boarding school and facing their destiny as clones, they marvel at aspects of the world the rest of us take for granted, such as shopping in a cheap Woolworths or looking at the ocean. They dream of working as cashiers or in an office, but such simple paths are closed to them. Mostly, they would like a little more time to live and love, but that, too, is denied them.

The tone gets even sadder and more poignant as Kathy becomes a carer for Ruth and Tommy as they undergo the operations that will harvest their body parts and soon enough kill them. Ishiguro heightens the sadness by never having the characters complain about their fates and by having Kathy accentuate the positives. For example, Kathy notes squeezing Ruth's hand as she writhes in pain from the operation that kills her. She never notes that killing Ruth this way in cruel and unjust.

The sadness accentuates Ishiguro's critique of the way societies instrumentalize or label some people as existing only for the convenience of others. Its bittersweet theme is also universal: most of us may live longer lives, but our lives are as fleeting as the clones, with death awaiting us.