Antibody-based therapeutics enjoy considerable clinical and commercial successes as cancer treatments. However, they can also cause serious toxicities due to recognition of tumor-associated antigens in noncancerous tissues, which can prevent antibody use in certain patient populations and therapeutic modalities. Here, we discuss recent efforts to develop advanced antibody therapeutics with activities restricted to the solid tumor microenvironment. With the intent of decreasing toxicities and expanding therapeutic windows, protein engineering strategies can render ligand binding sensitive to multiple tumor-specific characteristics. These triggers can be intrinsic to solid tumor microenvironments, such as low pH, high extracellular ATP, and the presence of specific proteases. Emerging strategies rely instead on exogenous triggers such as light and ultrasound to provide spatial and temporal control over antibody activation. These multilayered approaches to targeting diseased tissues are expected to usher in a new generation of precision therapeutics. •Antibodies elicit side effects by binding tumor-associated antigens on healthy cells.•Unique chemical features of solid tumors can be exploited to increase selectivity.•Antibodies activated by tumor-specific proteases are progressing in the clinic.•Antibodies activated by low pH or high ATP show promise for increased specificity.•Physical cues such as light and ultra-sound may support tumor-specific therapies.