Sponges represent an important component of benthic communities worldwide, but especially on tropical coral reefs. Their ecology has received an even higher awareness in the last decade since global change seems to favor and, consequently, increase sponge abundance. One important factor that allows the thriving of sponges is their potent chemistry. Sponge chemical defenses have been intensively studied over the last decades. It has been demonstrated repeatedly that sponges are often effectively defended against various biotic pressures and many defensive metabolites have been identified. However, it became more and more apparent that sponge defenses are not produced at constant rates but are often controlled in a highly regulated system affected by physiological or morphological characteristics, as well as environmental biotic and abiotic conditions. This chapter summarizes how sponge chemistry varies spatially over regional, local, and individual scales. It also discusses temporal variations in sponge bioactivities that are related to seasonality or defensive strategies like induced or activated defense. Based on these studies a conceptual model was developed that summarizes the conditions affecting the production of sponge secondary metabolites both in space and time. Natural and anthropogenic factors are discussed as promoters of increased variability of sponge defenses. We suggest that these interacting effects provide the basis for multifactorial studies that are needed to gain a better understanding of sponge chemical ecology and the chemical defense mechanisms that structure sponge populations and benthic sessile invertebrate communities.