Despite existing in large numbers with great heterogeneity, neurons form activity clusters in response to specific stimulus inputs. These activity clusters, also called engrams, are functional units that encode information at the cell and circuitry levels. Cell activation generally induces elevated CREB level, IEG expression and Ca2+ influx, from which a variety of activity-dependent tools have been developed. These tools are widely used in memory engram and neural ensemble research. In this article, we review the principles and applications of these activity-dependent tools, including LacZ-Daun02 inactivation system, CREB overexpression system, TetTag, TRAP, CANE, two synthetic activity-regulated promoters: E-SARE and RAM, and two calcium- and light- gated tools: Cal-light and FLARE. We also discuss the future development of activity-dependent tools.