Rottlerin and curcumin are natural plant polyphenols with a long tradition in folk medicine. Over the past two decades, curcumin has been extensively investigated, while rottlerin has received much less attention, in part, as a consequence of its reputation as a selective PKCδ inhibitor. A comparative analysis of genomic, proteomic, and cell signaling studies revealed that rottlerin and curcumin share a number of targets and have overlapping effects on many biological processes. Both molecules, indeed, modulate the activity and/or expression of several enzymes (PKCδ, heme oxygenase, DNA methyltransferase, cyclooxygenase, lipoxygenase) and transcription factors (NF-κB, STAT), and prevent aggregation of different amyloid precursors (α-synuclein, amyloid Aβ, prion proteins, lysozyme), thereby exhibiting convergent antioxidant, anti-inflammatory, and antiamyloid actions. Like curcumin, rottlerin could be a promising candidate in the fight against a variety of human diseases.