In every bit of honest writing in the world there is a base theme. Try to understand men, if you understand each other you will be kind to each other. Knowing a man well never leads to hate and nearly always leads to love. There are shorter means, many of them. There is writing promoting social change, writing punishing injustice, writing in celebration of heroism, but always that base theme. Try to understand each other.— John Steinbeck in his 1938 journal entry
Steinbeck emphasizes aspirations throughout the book. George aspires to become independent, to be his own boss, to have a homestead, and, most important, 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, security, and most of all, acceptance. Curley's wife dreams to be an actress, to satisfy her desire for fame lost when she married Curley, and an end to her loneliness.
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 anybody. Don't make any difference who the guy is, long's he's with you." 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 loneliness is sustained through 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 earn enough money to fulfill their dream. 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 cannot do so, the real danger of Lennie's mental handicap comes to the fore.
Regarding human interaction, the evil of oppression and abuse is a theme that is illustrated through Curley and Curley's wife. Curley uses his aggressive nature and superior position in an attempt to take control of his father's farm. He constantly reprimands the farm hands and accuses some of fooling around with his wife. Curley's Napoleon complex is evidenced by his threatening of the farm hands for minuscule incidents. Curley's wife, on the other hand, is not physically but verbally manipulative. She uses her sex appeal to gain some attention, flirting with the farm hands. According to the Penguin Teacher's Guide for Of Mice and Men, Curley and Curley's wife represent evil in that both oppress and abuse the migrants in different ways.
Fate is felt most heavily as the characters' aspirations are destroyed when 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.
Of Mice and Men can be associated with the idea that inherent limitations exist and despite all the squirming and struggling, sometimes the circumstances of one's existence limits their capacity to live the fairy tale lives they wish to. Even the title of the novel itself references this "the title is, of course, a fragment from the poem lay Robert Burns, which gives emphasis to the idea of the futility of human endeavor or the vanity of human wishes".
Animals play a role in the story as well; the heron shifts from a beautiful part of the scenery from the beginning of the novel to a predator near the end. The ending chapter has the heron return, preying upon snakes that get too curious in a repetitive nature, symbolic of the dreams of men constantly being snatched away.