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Freshwater and marine harmful algal blooms are expanding on a global scale. Recent reports of toxic events have sparked a growing awareness of the importance of cyanobacteria and cyanotoxins at the land-sea interface and estuaries in general. A recent survey in the Southern California Bight documented a wealth of cyanobacteria-dominated communities at a variety of locations. To gain further insight into these assemblages, we repeatedly sampled several sites with different proximity and degrees of connectivity to the Pacific Ocean in four coastal watersheds along the coast of southern California. Our findings revealed temporal and spatial heterogeneity in the occurrence of potential toxin-producing cyanobacteria and associated toxins. Multiple toxins were measured in 45% of all samples (and 25% of shellfish examined), including samples testing positive for anatoxin-a, cylindrospermopsin, three congeners of microcystins, or the eukaryotic toxin domoic acid. The ecosystems are hydrologically connected to the Pacific Ocean and provide a source of cyanotoxins to marine and estuarine environments. Collectively, potential toxin-producing cyanobacteria were prevalent at all study sites and appeared to persist throughout the year in some locations. These findings indicate a need for implementation of coordinated monitoring programs across the land-sea interface.