Steinbeck emphasizes dreams throughout the book. George aspires to independence, to be his own boss, to have a homestead, and most importantly to be "somebody". Lennie aspires to be with George on his independent homestead, and to quench his fixation on soft objects. Candy aspires to reassert his responsibility lost with the death of his dog, and for security for his old age ? on George's homestead. Crooks aspires to a small homestead where he can express self-respect, acceptance, and security. Curley's wife dreams to be an actress, to satisfy her desire for fame lost when she married Curley.

Loneliness is a significant factor in several characters' lives. Candy is lonely after his dog is gone. Curley's wife is lonely because her husband is not the friend she hoped for ?- she deals with her loneliness by flirting with the men on the ranch, which causes Curley to increase his abusiveness and jealousy. The companionship of George and Lennie is the result of loneliness. Crooks states the theme candidly as "A guy goes nuts if he ain't got nobody. Don't make no difference who the guy is, long's he's with you."[6] The author further reinforces this theme through subtle methods by situating the story near the town of Soledad, which means "solitude" in Spanish.

Despite the need for companionship, Steinbeck emphasizes how the nature of loneliness is sustained though the barriers established from acting inhuman to one another. The loneliness of Curley's wife is upheld by Curley's jealousy, which causes all the ranch hands to avoid her. Crooks's barrier results from being barred from the bunkhouse by restraining him to the stable; his bitterness is partially broken, however, through Lennie's ignorance.

Steinbeck's characters are often powerless, due to intellectual, economic, and social circumstances. Lennie possesses the greatest physical strength of any character, which should therefore establish a sense of respect as he is employed as a ranch hand. However, his intellectual handicap undercuts this and results in his powerlessness. Economic powerlessness is established as many of the ranch hands are victims of the Great Depression. As George, Candy and Crooks are positive, action- oriented characters, they wish to purchase a homestead, but because of the Depression, they are unable to generate enough money. Lennie is the only one who is basically unable to take care of himself, but the other characters would do this in the improved circumstances they seek. Since they can not do so, the real danger of Lennie's mental handicap comes to the fore.

Fate is felt most heavily as the characters' aspirations are destroyed as George is unable to protect Lennie (who is a real danger). Steinbeck presents this as "something that happened" or as his friend coined for him "non-teleological thinking" or "is thinking", which postulates a non-judgmental point of view.