Single-photon emission computed tomography (SPECT) is the state-of-the-art imaging modality in nuclear medicine, although only a few new SPECT tracers have become available in the past 20 years. Critical for the future success of SPECT is the design of new and specific tracers for the detection, localization, and staging of a disease and for monitoring therapy. The utility of SPECT imaging to address oncologic questions is dependent on radiotracers that ideally exhibit excellent tissue penetration, high affinity to the tumor-associated target structure, specific uptake and retention in the malignant lesions, and rapid clearance from non-targeted tissues and organs. In general, a target-specific SPECT radiopharmaceutical can be divided into two main parts: a targeting biomolecule (e.g., small molecular compound, peptide, antibody fragment) and a γ-radiation-emitting radionuclide (e.g., 99mTc, 123I). If radiometals are used as the radiation source, a bifunctional chelator is needed to link the radionuclide to the targeting entity. In a rational SPECT tracer design, these single components have to be critically evaluated in order to achieve a balance among the demands for adequate target binding and a rapid clearance of the radiotracer. In recent years, the theranostic combination of γ-emitters with therapeutic radionuclides (α, β−) was forced. The focus of this chapter is to depict recent developments of tumor-targeted SPECT radiotracers for imaging of cancer diseases. Possibilities for optimization of tracer design and potential causes for design failure are discussed and highlighted with selected examples.