One does not need to read or know anything about the Sluggy webcomic in order to play the game, but the knowledge is useful for setting up deeper strategies.
A Get Nifty game lasts at least an hour, depending on how many people are playing. The ultimate goal of the game is to win attacks of Danger and Boredom to Get Safe and Weird and further defending those states while accumulating the necessary points to "Get Nifty". Players use characters and objects, each with their own points of danger, niftiness, weirdness, and safety, to attack each other or themselves in order to achieve the basic states before being allowed to accumulate Niftiness. Other players may interfere or be requested to interfere by adding to attacking or defending points or by even changing the plot (overall stage and base statistics and constant effects).
Most cards have special effects to them, ranging from canceling others to sorting through either the draw or discard decks. Players should be aware of what affects what before considering playing certain attacks as these can significantly change the course of the game. For example, Oasis returns to her player's hand unless she succeeds in battle and Aylee can override the Playstayshun 2 (which gives infinite weirdness, giving immunity to boredom attacks). A card that would be canceled by one that is already in play is canceled the moment it comes into play, and should also be taken into account.