With each enemy that reaches the core, the condition of the core degrades from 100% when the condition reaches 0%, the game ends. In the extermination phase, a wave of one or more enemy types moves across the level towards the core. Building and upgrading both cost points, which are gained when enemies are killed.

The player can also upgrade any of the 3 weapons equipped at the start. These towers include stationary weapons, teleporters for the player's use, and pads that affect enemies moving over them. In the building phase, the player builds structures on a pre-defined grid, using the 8 'towers' chosen at the start of the level. The gameplay in Sanctum can be divided into the building phase and the extermination phase. To accomplish this, the player builds defensive structures, and assists their structures by fending off the enemies themselves.

To be successful in the task, the player will have to defend a 'core' on each level. In Sanctum, players take on the role of Skye, an elite soldier sent out to protect her home town, Elysion One, from hordes of mysterious alien creatures.

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