A variety of distinct and redundant mechanisms support tumour propagation and survival. Tumour parenchyma consists of a variety of geographically diverse cells with varying genetic expression among subclonal populations. Additionally, the solid tumour microenvironment consists of a dense network of stromal, vascular and immune cells altered by a number of mechanisms not only to tolerate but often to enhance cancer growth. The limited spectrum of chimaeric antigen receptor (CAR) T-cell specificity in the face of this dynamic landscape is one of the greatest challenges facing CAR T-cell therapy for solid tumours. Thus targeting multiple cancer-specific markers simultaneously could result in improved efficacy by broadening the therapeutic reach to include multiple subclonal populations of the tumour parenchyma as well as elements of the tumour microenvironment. Over the last 10 years, we and others have developed multiplex platforms that target the tumour profile rather than single tumour-restricted antigens. These platforms introduce a new dimension that may be key to the successful development of T-cell therapies for solid tumours and to the mitigation of relapses due to antigen escape.