The word epigenetics originated from Greek ἐπί, epì, “above,” and γεννητικός, gennetikòs, “relating to family inheritance,” literally above the genome. This term was first introduced in the scientific field by Conrad Hal Waddington, in 1942, to define the mechanisms of heritable phenotypic changes in a cell or organism due to activation/inactivation of certain genes, without involving changes in their structure. Epigenetic processes are involved as a causative part of different pathologies, e.g., cancer diseases. The study of genotype–phenotype relationships represents a hallmark in drug discovery, especially in the development of anticancer drugs. In the last decades, considerable efforts have been conducted to investigate the major epigenetic mechanisms, e.g., DNA methylation, post-translational modifications of the histones, RNA modifications, and chromatin remodeling, and to study how they occur, together with environmental factors, in initiation, progression, and invasion of carcinogenesis. In this context, targeting the players of such mechanisms (e.g., “readers,” “erasers,” and “writers”), and, specifically, inhibiting their activity or even leading to their degradation, have been shown to be promising strategies for the treatment of various cancer diseases. Among the potential routes to achieve inhibition or degradation of epigenetic players, two main approaches have been developed, i.e., (a) the discovery of small molecules, capable of blocking the activity of certain protein targets, and (b) the development of chemical degraders (e.g., PROTACs), which are generally heterobifunctional molecules capable of binding the protein of interest and exploiting cellular mechanisms to bring it to degradation, through binding to a protein partner involved in degradation processes (e.g., ubiquitination). This chapter will discuss the main epigenetic readers involved in different cancer pathologies and medicinal chemistry strategies to identify molecules or chemical degraders that can interact with them and fix the altered activity of a given epigenetic pathway responsible for the onset and maintenance of different cancers.