Adoptive cell therapy with gene-engineered T cells bearing antitumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a promising and rapidly evolving field of translational medicine. This approach has delivered exciting responses for some patients with lymphoid hematologic neoplasms, leading to recent US Food and Drug Administration approvals. Hematopoietic stem cellular gene therapy has also shown promising advances, with durable and potentially curative clinical benefit and without the potential toxicities of allogeneic hematopoietic cell transplant. However, for both of these novel strategies, many questions remain unanswered. Compared to synthetic viral gene addition therapy (e.g., CAR T-cell engineering), translation of gene-editing technologies to patient care is in its infancy. Multiple clinical trials are ongoing or expected to open for CAR T cell and inherited monogenic disorders (Gardner et al., Blood 129:3322–3331, 2017) (refer to subsequent disease-specific chapters in the book). In this chapter, we will highlight the most recent and clinically relevant developments in the arena of gene-modified T-cell-based therapies and hematopoietic stem cellular gene therapy specifically focusing on hematologic disorders. We will conclude the chapter by summarizing the apparent challenges and directions for the future.