The specific microenvironment that cells reside in fundamentally impacts their broader function in tissues and organs. At its core, this microenvironment is composed of precise arrangements of cells that encourage homotypic and heterotypic cell-cell interactions, biochemical signaling through soluble factors like cytokines, hormones, and autocrine, endocrine, or paracrine secretions, and the local extracellular matrix (ECM) that provides physical support and mechanobiological stimuli, and further regulates biochemical signaling through cell-ECM interactions like adhesions and growth factor sequestering. Each cue provided in the microenvironment dictates cellular behavior and, thus, overall potential to perform tissue and organ specific function. It follows that in order to recapitulate physiological cell responses and develop constructs capable of replacing damaged tissue, we must engineer the cellular microenvironment very carefully. Many great strides have been made toward this goal using various three-dimensional (3D) tissue culture scaffolds and specific media conditions. Among the various 3D biomimetic scaffolds, synthetic hydrogels have emerged as a highly tunable and tissue-like biomaterial well-suited for implantable tissue-engineered constructs. Because many synthetic hydrogel materials are inherently bioinert, they minimize unintentional cell responses and thus are good candidates for long-term implantable grafts, patches, and organs. This review will provide an overview of commonly used biomaterials for forming synthetic hydrogels for tissue engineering applications and techniques for modifying them to with bioactive properties to elicit the desired cell responses.